WO2010136493A1 - Substituted aminopropionic derivatives as neprilysin inhibitors - Google Patents

Substituted aminopropionic derivatives as neprilysin inhibitors Download PDF

Info

Publication number
WO2010136493A1
WO2010136493A1 PCT/EP2010/057247 EP2010057247W WO2010136493A1 WO 2010136493 A1 WO2010136493 A1 WO 2010136493A1 EP 2010057247 W EP2010057247 W EP 2010057247W WO 2010136493 A1 WO2010136493 A1 WO 2010136493A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
halo
nmr
mhz
ppm
Prior art date
Application number
PCT/EP2010/057247
Other languages
French (fr)
Inventor
Gary Mark Coppola
Yuki Iwaki
Rajeshri Ganesh Karki
Toshio Kawanami
Gary Michael Ksander
Muneto Mogi
Original Assignee
Novartis Ag
Sun, Robert
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=42313042&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2010136493(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to PL10720165T priority Critical patent/PL2435409T3/en
Priority to ES10720165.9T priority patent/ES2523734T3/en
Priority to MEP-2014-140A priority patent/ME01923B/en
Priority to UAA201114061A priority patent/UA106233C2/en
Priority to MX2011012628A priority patent/MX2011012628A/en
Priority to CN201080032688.1A priority patent/CN102574801B/en
Priority to EP10720165.9A priority patent/EP2435409B1/en
Priority to JP2012512359A priority patent/JP5420761B2/en
Priority to RS20140576A priority patent/RS53664B1/en
Priority to BRPI1011657-5A priority patent/BRPI1011657A2/en
Priority to KR1020117031124A priority patent/KR101442897B1/en
Priority to DK10720165.9T priority patent/DK2435409T3/en
Priority to AU2010251967A priority patent/AU2010251967B9/en
Priority to SI201030778T priority patent/SI2435409T1/en
Application filed by Novartis Ag, Sun, Robert filed Critical Novartis Ag
Priority to SG2011083094A priority patent/SG176009A1/en
Priority to NZ596304A priority patent/NZ596304A/en
Priority to EA201101671A priority patent/EA019511B1/en
Priority to CA2763572A priority patent/CA2763572C/en
Publication of WO2010136493A1 publication Critical patent/WO2010136493A1/en
Priority to ZA2011/08222A priority patent/ZA201108222B/en
Priority to IL216367A priority patent/IL216367A0/en
Priority to TNP2011000592A priority patent/TN2011000592A1/en
Priority to CU2011000217A priority patent/CU24051B1/en
Priority to MA34458A priority patent/MA33636B1/en
Priority to HRP20141050AT priority patent/HRP20141050T1/en
Priority to SM201400175T priority patent/SMT201400175B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/49—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/56—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • Atrial natriuretic peptides also called atrial natriuretic factors (ANF) have diuretic, natriuretic and vasorelaxant functions in mammals.
  • ANF peptides is metabofically inactivated, in particular by a degrading enzyme which has been recognized to correspond to the enzyme neutral endopeptidase (NEP) EC 3.4,24.11 , also responsible for e.g. the metabolic inactivation of enkephalins.
  • NEP neutral endopeptidase
  • Neutral endopeptidase (EC 3.4.24.11; enkephalinase; atriopeptidase; NEP) is a zinc- containing metalloprotease that cleaves a variety of peptide substrates on the amino side of hydrophobic residues [see Pharmacol Rev, Vol. 45, p. 87 (1993)].
  • Substrates for this enzyme include, but are not limited to, atrial natriuretic peptide (ANP, also known as ANF), brain natriuretic peptide (BNP), met- and leu-enkephalin, bradykinin, neurokinin A, endothelin-1 and substance P.
  • ANP is a potent vasorelaxant and natriuretic agent [see J Hypertens, Vol. 19, p. 1923 (2001)]. Infusion of ANP in normal subjects resulted in a reproducible, marked enhancement of natriuresis and diuresis, including increases in fractional excretion of sodium, urinary flow rate and glomerular filtration rate [see J CHn Pharmacol, Vol. 27, p. 927 (1987)]. However, ANP has a short half-life in circulation, and NEP in kidney cortex membranes has been shown to be the major enzyme responsible for degrading this peptide [see Peptides, Vol. 9, p. 173 (1988)]. Thus, inhibitors of NEP (neutral endopeptidase inhibitors, NEPi) should increase plasma levels of ANP and, hence, are expected to induce natriuretic and diuretic effects.
  • NEPi neutral endopeptidase inhibitors
  • This enzyme is involved in the breakdown of several bioactive oligopeptides, cleaving peptide bonds on the amino side of hydrophobic amino acid residues.
  • the peptides metabolised include atrial natriuretic peptides (ANP), bombesin, bradykinin, calcitonin gene- related peptide, endothelins, enkephalins, neurotensin, substance P and vasoactive intestinal peptide.
  • the aim of the present invention is to provide novel compounds which are useful as neutral endopeptidase inhibitors, e.g. as inhibitors of the ANF-degrading enzyme in mammals, so as to prolong and potentiate the diuretic, natriuretic and vasodilator properties of ANF in mammals, by inhibiting the degradation thereof to less active metabolites.
  • the compounds of this invention are thus particularly useful for the treatment of conditions and disorders responsive to the inhibition of neutral endopeptidase (NEP) EC 3.4.24.11.
  • the compounds of the invention by inhibiting the neutrai endopeptidase EC.3.4.24.11, can potentiate the biological effects of bioactive peptides.
  • the compounds have utility in the treatment of a number of disorders, including hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supra
  • the compounds of the invention may have activity in other therapeutic areas including for example the treatment of menstrual disorders, preterm labour, pre-eclampsia , endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovarian syndrome, implantation failure).
  • the compounds of the invention should treat asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure sores), septic shock, the modulation of gastric acid secretion, the treatment of hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications and athereosclerosis, male and female sexual dysfunction, In a preferred embodiment the compounds of the invention are useful in the treatment of cardiovascular disorders.
  • the invention pertains to the compounds, methods for using them, and uses thereof as described herein.
  • Examples of compounds of the invention include the compounds accoring to anyone of Formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof, and the compounds of the examples.
  • the invention therefore provides a compound of the formula (P):
  • R 1 is H, C 1-7 alkyl, hydroxy, C 1-7 alkoxy, halogen, -SH, -S-CwaikyJ or NR a R b ;
  • R 2 for each occurence is independently d. 7 alky ⁇ , halo, NO 2 , CN 1 C 1-7 aJkanoylamino, C 3 .
  • R 3 is A 1 -C(O)X 1 or A ? -R 4 ;
  • R 4 is C ⁇ . t oaryl or a heteroaryl, which can be monocyclic or bicyclic, and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, hydroxyC/alkyl, nitro, -NR a R b , -C(O)C 1-7 alkyi, C(O)-O-Cwalkyl, C 1-
  • R 4 is a heterocyclyl which can be optionally substituted with one or more substituents independently selected from the group consisting of oxo, hydroxy, hydroxyC 1-
  • R s is H, halo, hydroxy, C 1-7 alkoxy, halo, C 1- ?alkyf or halo-C 1-7 akyl;
  • X and X 1 are independently OH, -O-C 1-7 alkyl, -NR 9 R 6 , -NHS(O) 2 -C 1-7 alkyl, -NHS(O) 2 -benzyl or -O- C ⁇ -ioaryl; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C ⁇ aryl, heteroaryl, heterocyclyl,
  • B 1 is -C(O)NH- or -NHC(O)-;
  • a 1 is a bond or a linear or branched C 1-7 alkylene ; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C 3 . ⁇ cycioalkyt,
  • a 1 is a linear or branched C 1-7 alkenylene
  • a 1 is a linear 0 %A alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NR C ; and A 1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and C 1 ⁇ alkyl; in which
  • R c for each occurrence is independently H, d.yalkyl, -C(O)-O-C ⁇ alkyl or -CH 2 C(O)OH; or
  • a 1 is a phenyl or a heteroaryl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of C 1-7 alkyl, C ⁇ cycloalkyi, haio-Cwafkyl, hydroxy, C 1 ⁇ aIkOXy, halo, -NR a R b , -OCH 2 CO 2 H 1 and -OCH 2 C(O)NH 2 ; or
  • a 1 is a C ⁇ cycloalkyl
  • a 1 is -C 1 ⁇ alkylene-Cg.io-aryl-, -C M alkylene-heteroaryl- or -C t ⁇ alkylene-heterocyclyi-, wherein
  • a 1 may be in either direction
  • a 2 is a bond or a linear or branched C 1- ? alkylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1- 7aikoxy, hydroxy, O-Acetate and Cs.rcycloalkyl; n is O, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocycfyi is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S.
  • the invention therefore provides a compound of the formula (I);
  • R 1 is H or C ⁇ alkyl
  • R 2 for each occurence is independently C 1-7 alkyl, halo, NO 2 , CN. C 1-7 alkanoylamino, C 3 .
  • R 3 is A 1 -C(0)X 1 or A 2 ⁇ R 4 ;
  • R 4 is C 6 .ioary! or a heteroaryl, which can be monocyclic or bicycfic, and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, hydroxyd-yalkyi, amino, C(O)-O- d ⁇ alkyf, d ⁇ aJkoxy, halo, C 1-7 aikyl, halo-C 1-7 akyl, C 6 .i 0 aryi, heteroaryl, -NHSO K -C 1-7 alky!
  • R 4 is a heterocyclyi which can be optionally substituted with one or more substituents independently selected from the group consisting of oxo, hydroxy, hydroxyC 1-7 alkyl, amino, C(O)-O- d. 7 a!kyl, d.yalkoxy, halo,
  • R ⁇ is H, halo, hydroxy, C 1-? aikoxy, halo, C 1-7 aikyl or halo-d- 7 akyl;
  • X and X 1 are independently OH, -O-C ⁇ alkyl, NR a R b , or -O- C 6 .ioaryi; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ce-ioaryl, heteroaryl, heterocyclyi, C(O)NH 2 , C(O)NH- C,. ⁇ alkyl, and C(O)N(C 1- ea!kyl) 2 ;
  • B 1 is -C(O)NH- or -NHC(O)-;
  • a 1 is a bond or a linear or branched C t . 7 aikylene ; which is optionally substituted with one or more substituents independently selected from the group consisting of haio, C 3 . 7 cycioalkyl,
  • a 1 is a phenyl or a heteroaryl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of C h alky!, C ⁇ -cycloalkyl, halo-C 1-7 aikyl, hydroxy, C 1-7 afkoxy, halo, ⁇ NR a R b , -OCH 2 CO x H, and -OCH 2 C(O)NH 2 ; or
  • a 1 is a C 3 . 7 cycloalkyl
  • a 1 is -C 1 ⁇ alkylene-C ⁇ . 10 -aryl-, -d ⁇ alkylene-heteroaryi- or -C 1 ⁇ alkylene-heterocyclyl-, wherein
  • a 1 may be in either direction
  • a 2 is a bond or a linear or branched C 1- ? alkylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-7 alkoxy, hydroxy, O-Acetate and Cs.7cycioafkyl; n is 0, 1, 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicycltc aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S,
  • the invention pertains to a method for treating a disorders or diseases responsive to the inhibition of neutral endopeptidase EC 3.4. 24.11 (NEP) 1 in a subject, by administering to the subject a therapeutically effective amount of a compound according to anyone of Formulae V and I to VIIC. or a pharmaceutically acceptable salt thereof, such that the disorder or disease responsive to the inhibition of neutral endopeptidase EC 3.4. 24.11 (NEP) in the subject is treated.
  • the invention pertains to a method for treating hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathey, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis.atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (M
  • the invention pertains to pharmaceutical compositions, comprising of a compound according to anyone of Formulae I 1 and I to VIIC, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the invention pertains to combinations including a compound according to anyone of Formulae V and I-VIC, or a pharmaceutically acceptable salt thereof, and pharmaceutical combinations of one or more therapeutically active agents.
  • the invention pertains to a method for inhibiting neutral endopeptidase EC 3,4. 24.11 in a subject by administering to the subject a therapeutically effective amount of a compound according to anyone of Formulae i' and I to VIIC, or a pharmaceutically acceptable salt thereof, such that neutral endopeptidase EC 3.4, 24,11 is inhibited.
  • the invention provides a compound of the Formula I or !', or a pharmaceutically acceptable salt thereof, wherein: R 1 is H or C 1 ⁇ aIkVl;
  • R 2 for each occurence is independently C 1 ⁇ alkyl, halo, Ca. 7 cycloalkyl, hydroxy, C 1-7 aikoxy, haloC 1-7 alkyl, ⁇ NR a R b , C 6 .ioaryl, heteroaryl or heterocyclyl; wherein R a and R b for each occurence are independently H or C 1 ⁇ alkyl; R 3 is A 1 -C(O)X 1 or A 2 ⁇ R 4 ; R 4 is Ce-ioaryl or a heteroaryl, which can be monocyclic or bicycftc and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, C 1-7 alkoxy, halo, d. ⁇ alkyi, halo-C 1-7 akyl C 6 -ioaryl, heteroaryl, -NHSO 2 - d. 7 alkyl and benzyl;
  • R 5 is H
  • X and X 1 are independently OH, -O-C 1-7 a!kyl or NR s R b ;
  • B 1 is -C(O)NH- or -NHC(O)-;
  • a 1 is a linear or branched C 1-7 alkylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C ⁇ cycloalkyi, C 1-
  • a 1 is a phenyl or a heteroaryl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of C h alky!, C 3 .7cycloaJkyl, halo-C 1-7 aikyl, hydroxy, C 1-7 alkoxy, halo, -NR*R b , -OCH 2 CO 2 H, and -OCH 2 C(O)NH 2 ; and
  • a 2 is a bond or a linear or branched C 1-/ alkyfene: which is optionally substituted with one or more substituents independently selected from the group consisting of hafo, C 1-7 alkoxy, hydroxy ⁇ O-Acetate and C ⁇ cycloalkyl; and n is 0, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms. wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S.
  • Certain compounds of Formula I or I' include compounds of Formula IA wherein the stereochemistry at the carbon bearing the biphenyl group is (R):
  • Formula IA or a pharmaceutically acceptable salt thereof, wherein X, R 1 , R 2 , B 1- R 3 and n have the definitions of Formula I or I', supra.
  • the invention pertains to compounds of Formula I or I' or a pharmaceutically acceptable salt thereof, wherein n is 1 , 2, 3, 4 or 5; R 2 is halo and is attached to the meta position and the other optional R z groups are independently C 1-7 alkyl. NO 2 , CN 1 halo, C 3-7 cycloalkyl, hydroxy, C 1 ⁇ aIkOXy, halo-C v7 alkyl, NR b R c , C 6 ioaryl, heteroaryl or heterocyclyl.
  • This embodiment is illustrated by compounds of Formulae IB and IC:
  • Formula IB Formula IC or a pharmaceutically acceptable salt thereof, wherein X 1 R 1 , R 2 , B 1 , R 3 have the definitions of Formula I or I 1 , supra: p is 0, 1, 2, 3 or 4 and R 2a is halo.
  • Certain compounds of Formula I or C include compounds of Formula II.
  • the invention pertains to compounds of Formula M wherein the stereochemistry of the carbon bearing the biphenyi groups is (R).
  • This embodiment is illustrated by compounds of Formula HA:
  • Formula HA or a pharmaceutically acceptable salt thereof, wherein X, X 1 , A 1 , R 1 , R 2 and n have the definitions of Formula I or ⁇ , supra.
  • Certain compounds of Formula I, I 1 or Il include compounds of Formula MB or HC:
  • Formula HB Formula HC or a pharmaceutically acceptable salt thereof, wherein X, X ⁇ A 1 , R 1 , R 2 have the definitions of Formula I or I', supra; p is 0, 1 , 2, 3 or 4 and R 2a is halo.
  • aste compounds of Formula I or I' include compounds of Formula III:
  • Formula III or a pharmaceutically acceptable salt thereof, wherein X 1 X 1 , A 1 , R 1 , R J and n have the definitions of Formula I or I', supra
  • the invention pertains to compounds of Formula III wherein the stereochemistry of the carbon bearing the biphenyl groups is (R). This embodiment is illustrated by compounds of Formula IHA
  • Formula IMA or a pharmaceutically acceptable salt thereof, wherein X, X 1 .
  • a ⁇ R 1 , R 2 and n have the definitions of Formula I or I 1 , supra
  • Certain compounds of Formula Mf include compounds of Formula 1MB or IMC:
  • Formula IHB Formula IMC or a pharmaceutically acceptable salt thereof, wherein X, X 1 , A 1 , R 1 , R 7 have the definitions of Formula I or I 1 , supra, p is 0, 1, 2, 3 or 4 and R Za is halo.
  • the invention provides a compound according to anyone of formulae I ' , I to IC, Ii to HC and IM to MIC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is a linear C ⁇ alkylene, which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1 ⁇ aIkOXy, hydroxy, O-acetate and C 3 . 7 cycloaikyl; in which two geminal alkyl can optionally combine to form a C 3-7 cycloalkyl.
  • a further embodiment include compounds according to anyone of Formulae I', I to IC, Ii to HC and tli to IHC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt thereof, wherein A 1 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or A 1 has the following formulae:
  • R d1 , R 02 , R e ⁇ R e2 , R e3 and R e4 are independently H, halo, C ⁇ cycloalkyl, or C 1-7 alkyl; and alternatively R c1 and R 02 or R d1 and R d2 can form together with the atoms to which they are attached a Cs ⁇ cycloalkyl.
  • a 1 is one of the following:
  • Yet another further embodiment includes compounds according to anyone of Formulae I', I to IC, Il to HC and III to IHC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt thereof, wherein A 1 has the following formulae:
  • R' ⁇ R ⁇ , R ⁇ and R f4 are independently H, halo, O-acetate or C 1- ralkyl.
  • a 1 is one of the following: or
  • the invention provides a compound according to anyone of of Formulae !', I to IC.
  • Examples of this embodiment are compounds of anyone of Formulae I'. I to IC, Il to MC and III to IKC, wherein A1 is selected from the following:
  • the invention provides a compound according to anyone of of Formulae I', I to IC 1 Il to HC and III to HIC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is a linear or branched C 2 .raikenylene.
  • the invention provides a compound according to anyone of of Formulae I'. I to IC, Il to IIC and III to HIC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is a linear C1. 4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NR C ; and A 1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and C ⁇ alkyl; in which R c for each occurrence is indepenctenently H, C ⁇ alkyl, -C(O)O d.yalkyl or CH 2 C(O)OH.
  • One further embodiment includes compounds of Formulae I', I to IC 1 Il to IfC and ill to NIC wherein A 1 is one of the following:
  • the invention provides a compound according to anyone of of Formulae I', I to IC.
  • Certain compounds of the above embodiment include compounds according to anyone of Formula I', I to IC 1 H to HC and IH to IHC or a pharmaceutically acceptable salt thereof, wherein A 1 is a 5-membered ring heteroaryl.
  • This embodiment is illustrated by compounds of Formula IV:
  • Formuia IV or a pharmaceutically acceptable salt thereof wherein X, X 1 , B 1 , R 1 , R 2 and n have the definitions of Formula I or I", supra and and Y 1 , Y 2 and Y 3 are independently N 1 NH, S, O or CH and form together with the ring atoms to which they are attached a 5-membered heteroaryl ring.
  • the invention pertains to compounds of Formula IVA:
  • Formula IVA or a pharmaceutically acceptable salt thereof wherein X, X ⁇ B 1 , R 1 , R 2 , Y 1 , Y 7 , Y 3 and n have the definitions of Formulae I, I' or IV. supra.
  • Y 1 , Y z and Y 3 form together with the ring atoms to which they are attached a 5-membered heteroaryl ring selected from furan, thiophene, pyrrofe, pyrazole, oxazote, thiazole, oxadiazole, thiadiazoie, and triazole.
  • One further embodiment includes compounds of Formula IV or ViA, or a pharmaceutically acceptable salt thereof, wherein the 5-membered heteroary! is one of the following:
  • the invention pertains to compounds of Formula IV or IVA wherein n is 1 , 2, 3, 4 or 5; R z is halo in the meta position and the other optional R 2 groups are independently C h alky!, NO*, CN, halo, C ⁇ cyctoalkyl, hydroxy, C 1 ⁇ aIkOXy, halo-d ⁇ alkyl, NR b R c , C 6 .i O aryl, heteroaryl or heterocyclyl.
  • the invention pertains to compounds of Formula P, I to IC, Il to HC or III to IHC 1 or a pharmaceutically acceptable salt thereof, wherein A 1 is a 5-membered ring heteroaryl attached to the amide B 1 at a nitrogen atom.
  • a 1 is a 5-membered ring heteroaryl attached to the amide B 1 at a nitrogen atom.
  • This embodiment is illustrated by compounds of Formulae V or VA:
  • Formula V Formula VA or a pharmaceutically acceptable salt thereof, wherein X, X 1 , B 1 , R 1 , R 2 and n have the definitions of Formula I or I', supra and each Y 4 are independently N, S 1 O or CH.
  • the invention pertains to compounds of Formula V or VA wherein n is 1 , 2, 3, 4 or 5; R 2 is halo in the meta position and the other optional R 2 groups are independently C ⁇ aikyi, NO ? , CN, haio, Ca ⁇ cycloafkyl, hydroxy, C 1-7 alkoxy, hafo-Cvralkyl, NR b R c , C ⁇ -toaryl, heteroaryl or heterocyclyl.
  • the invention provides a compound according to anyone of Formulae P, I to IC, Il to HC and III to HIC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is a phenyl or a 6-membered ring heteroaryl in which phenyl and heteroaryl are optionally substituted with d ⁇ aikyl, C 3 . 7 cycloalkyl, halo-C 1-7 alkyl, hydroxy, C ⁇ alkoxy, halo, NR a R b , -OCHjfCOjH, or -OCH x C(O)NHj.
  • One aspect of this embodiment include compounds according to anyone of Formulae I 1 , 1 to IC, If to HC and IM to HIC, or pharmaceutically acceptable salt thereof, wherein A 1 is connected to the amide B 1 and to the C(O)X 1 moieties in a para arrangement.
  • Another aspect of this embodiment include compounds according to anyone of Formula I', I to IC, Il to IfC and HI to HIC wherein A 1 is connected to the amide B 1 and to the C(O)X 1 moieties in a meta arrangement.
  • Compounds of this embodiment include compounds of Formula Vl.
  • Formula Vl or a pharmaceutically acceptable salt thereof, wherein X, X 1 , B 1 , R 1 , R 2 and n have the definitions of Formula I or I', supra and W 1 , W 2 , W 3 and W 4 are independently N or CR e , in which each R ⁇ is independently H, C ⁇ alkyi, C 3 .?cycloalkyl, halo-C h alky!, hydroxy, C 1- raikoxy, halo, -NR a Rb, -OCH 2 CO 2 H or -OCH 2 C(O)NH 2
  • a 1 is phenyl, pyridine or pyrimidine.
  • Formula VIA or a pharmaceutically acceptable salt thereof, wherein X, X 1 , B 1 , R 1 , R 2 , W 1 , W ? , W 3 and W 4 and n have the definitions of Formulae I 1 1 * or Vl, supra.
  • One further embodiment includes compounds of Formula Vl or VIA, or a pharmaceutically acceptable salt thereof, wherein A 1 is one of the following:
  • the invention pertains to compounds of Formula Vl or VIA, or a pharmaceutically acceptable salt thereof, wherein n is 1 , 2, 3, 4 or 5; R 2 is halo in the meta position and the other optional R 2 groups are independently C 1 ⁇ aIKyI, NO 2 , CN, halo, C 3- rcycloalkyl, hydroxy, C 1-7 alkoxy, halo-C ⁇ alkyl, NR b R c , CVioaryl, heteroaryl or heterocyclyl.
  • the invention pertains to compounds according to anyone of Formulae I', I to IC, IV to IVC, V to VC and Vl to VIC, or pharmaceutically acceptable salt thereof, wherein B 1 is -C(O)NH-. In another embodiment, B 1 is -NHC(O)-.
  • Certain compounds of the above embodiment include compounds according to anyone of Formulae I 1 , 1 to IC, Il to MC and III to IHC. or a pharmaceutically acceptable salt thereof, wherein A 1 is -d ⁇ alkylene-Ce-io-aryl-, -C M alkylene-heteroaryl- or -C 1 ⁇ alkylene- heterocyclyh -Ce-ioaryl-C ⁇ -alkylene-, -heteroaryl-C M alkylene or -heterocyclyl-C ⁇ alkylene-.
  • a 1 is -C 1 ⁇ aikylene-C fM o-aryl-, -C t ⁇ alkylene-heteroaryl- or - C M alkylene-heterocyclyk wherein the alkylene portion is attached to B 1 amide group and the aryl, heteroaryl or heterocyclyl moittes are attached to C(O)X 1 .
  • a 1 is -CH 2 -phenyl- or -phenyl-CH; ? -.
  • a 1 is -CH 2 -heteroaryi or -heteroaryl-CHa-.
  • a 1 is -CHz-heterocyclyl or -heterocyclyl-CHj-. Representative examples of A 1 are the following:
  • Formula VII or a pharmaceutically acceptable satt thereof, wherein X, A 2 , R 1 , R 2 , R 4 and n have the definitions of Formula I or I', supra.
  • a further embodiment includes compounds of Formula V(IA:
  • Formula VIIA or a pharmaceutically acceptable sait thereof, wherein X, A 2 , R 1 , R 2 , R 4 and n have the definitions of Formula I or V, supra.
  • Formula VIIB Formula Vl IC or a pharmaceutically acceptable salt thereof, wherein X 1 A 2 , R 1 , R 2 , R 4 have the definitions of Formula I or I', supra; p is 0, 1, 2, 3 or 4 and R 2a is halo.
  • a further aspect of this embodiment include compounds according to anyone of Formulae VII to VIIC 1 or a pharmaceutically acceptable salt therof, wherein A 2 is (CH 2 ) P and p is 0, 1 , 2, 3. In one aspect of this embodiment p is O 1 therefore A 2 is a bond. In another aspect of this embodiment A 2 is CH ⁇ or CH 2 -CH 2 .
  • the invention provide compounds according to anyone of Formulae VII to VIIC 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally substituted C$.i O aryl.
  • aryl are benzoimidazolone, benzoisothiazolone or phenyl.
  • R 4 is phenyl.
  • Substituents on the phenyl ring include for example, halo ⁇ e.g. F, Ci), hydroxy, halo-C )-7 alkyl (e.g. CF 3 ), -NHS(O) 2 -C 1-7 alkyl, heteroaryl, C 1-7 aikoxy or d. 7 alkyl.
  • the invention provides compounds according to anyone of Formula VII to VIIC or a pharmaceutically acceptable salt thereof, wherein R 4 is an optionally substituted bicyclic heteroaryl.
  • the invention provide compounds according to anyone of Formulae VII to VIIC or a pharmaceutically acceptable salt thereof wherein R 4 is optionally substituted 5- or 6-membered heteroaryl.
  • R ⁇ is a 6-membered ring heteroaryl selected from the group consisting of pyrazinyl, pyridinyl, pyrimidinyl, oxo-pyranyl (e.g. pyranone, optionally substituted pyran-4-one, pyran-2-one such as 3-hydroxy-pyran-4-one. 3-hydroxy-pyran-2-one), and oxo-pyridtnyl (e.g.
  • R 4 is a 5-membered ring heteroaryi selected from the group consisting of oxazole, pyrrole, pyrazole, isooxazoie, triazoie, tetrazole, oxacliazole (e.g. 1- oxa-3,4-diazote.
  • oxa-2,4-diazole 1-oxa-2,4-diazole
  • oxadiazolone ⁇ e.g. oxadiazol-2-one
  • thiazole isothiazofe, thiophene, imidazole and thiadiazole.
  • R* are oxazolone, thiazolone, oxadiazolone, triazolone, oxazoJone, imidazolone, pyrazolone.
  • the optional s ⁇ bstituents on C ⁇ -io ⁇ ryl and heteroaryl are selected from hydroxy, C 1-7 alkyl, C 1-7 aikoxy, halo, ha!o-C 1- ⁇ aikyt or benzyl.
  • the invention provide compounds according to anyone of Formulae VII to VIIC or a pharmaceutically acceptable salt thereof, wherein R 4 is a bicyclic heteroaryl.
  • a further embodiment includes compounds according to anyone of Formulae VII to VIIC, or a pharmaceutically acceptable salt thereof, wherein R" is indole, benzothiazole or benzimidazole.
  • Representative examples of R 4 are the following:
  • the invention provide compounds according to anyone of Formulae VII to VIIC, or a pharmaceutically acceptable salt thereof wheretn R 4 is a monocyclic saturated or partjaily saturated heterocyclyi, which heterocyclyl contains at least one heteroatom selected from nitrogen, sulfur and oxygen, and which heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of oxo, hydroxy, C 1-7 alkoxy, halo, C h alky!, halo-C 1- 7akyi, C 6 .i ⁇ aryl, heteroaryl, -NHSO 2 -C 1-7 afkyl and benzyl.
  • R 4 is pyrrolidine or imidazoline, wherein the heterocyclyl may be linked to the carbonyl (C(O)-A 2 ) moiety via a carbon or a nitrogen and the heterocyclyl ts optionally substituted with oxo.
  • the invention provide compounds according to anyone of Formulae l ⁇ I to IC, Il to MC, III to IHC IV, IVA 1 V, VA, Vl, VIA and VII to VIIC or a pharmaceutically acceptable salt thereof, wherein R 1 is H
  • the invention provide compounds according to anyone of Formulae I', I to IC, Il to HC 1 III to IMC, IV 1 IVA 1 V, VA, Vl, VIA and VII to VIIC, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently halo, C h alky!, C 1 ⁇ aIkOXy 1 hydroxy, halo-C 1 7 alkyl and n is O, 1 or 2 In a further embodiment n is 1, 2, 3, 4 or 5, R 2 is halo in the meta position and the other optional R 2 groups are independently halo, C 1-7 alkyl, C ⁇ ralkoxy, hydroxy or haloalkyl.
  • the invention provide compounds according to anyone of Formulae P 1 I to IC, Il to HC, Ml to IHC, IV, IVA, V 1 VA, Vl, VIA and VII to VIIC, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2, R 2 is meta-chloro or meta-fiuoro and the other optional R 2 group is halo, C 1-7 alkyt, C ⁇ aikoxy, hydroxy or haloalkyl.
  • the invention provide compounds according to anyone of Formulae P 1 1 to IC, Il to HC, IN to MfC, I 1 IVA, V, VA, Vl 1 VIA and VII to VIIC, or a pharmaceutically acceptable salt thereof, wherein X and X 1 are independently OH or -O-C 1- 7 alkyl (e.g. -O-ethyl, -O-methyl or ⁇ O-nbutyl). In one particular aspect of this embodiment X and X 1 are OH.
  • X and X 1 are independently -O-C 1- 7 alkyl in which alkyl is substituted with C ⁇ -ioaryl, heteroaryi, heterocyclyl, C(O)NH 2 , C(O)NH- C ⁇ alkyt, or C(O)N(C ⁇ alkyl) 2 .
  • Representative examples of X or X 1 are -O-CH 2 -C(O)N(CH 3 ) 2 , -O-CHa-CHa-morpholine, -O-CH 2 -dioxo ⁇ one or -O-benzyl.
  • X and X 1 are -O-C 6 .i ⁇ >aryl.
  • a representative examples of -0-C 6 .ioaryl is -O-(2,3- dihydro-1H-indene).
  • X, X 1 , B 1 , A 1 , A 2 , R 2 , R 1 and R A groups are those defined by the X, X 1 , A 1 . A 2 , B 1 . R 2 , R 1 and R 4 groups in the Examples section beiow.
  • the term '-alkyl refers to a fully saturated branched or unbranched (or straight chain or linear) hydrocarbon moiety, comprising 1 to 20 carbon atoms.
  • the alkyl comprises 1 to 7 carbon atoms, and more preferably 1 to 4 carbon atoms.
  • alkyl examples include methyl, ethyl, n-propyl, /so-propyl, n-butyl, sec-butyl, /so-butyl, tert-butyl, ⁇ -pentyl, isopentyl, neopentyl, n-hexyf, 3-methyJhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl.
  • C 1-7 alkyl refers to a hydrocarbon having one to seven carbon atoms.
  • alkenyl includes both "unsubstituted alkyls " and "substituted alkyls".
  • alkylene refers to a divalent alkyl radical, wherein alkyl is as previously defined.
  • alkenyT refers to a branched or unbranched hydrocarbon having at teast one carbon-carbon double bond.
  • C 2 - 7 aikenyr refers to a hydrocarbon having two to seven carbon atoms and comprising at least one carbon-carbon double bond.
  • Representative examples of alkenyi are vinyl, prop-1-enyl, alfyl, butenyl, isopropenyl or isobutenyl.
  • alkeylene refers to a divalent alkenyi radical, wherein alkenyi is as previously defined.
  • haloalkyl refers to an alkyl as defined herein.that is substituted by one or more halo groups as defined herein.
  • the haloalkyl can be monohaloaikyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
  • a monohaloalkyl can have one iodo, bromo, chloro or fiuoro within the alkyl group.
  • Dihaloalky and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.
  • the polyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.
  • Representative examples of haioalkyl are fluoromethyl. difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyi.
  • a perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms.
  • the term "halo-C h alky!” refers to a hydrocarbon having one to seven carbon atoms and being substituted by one or more halo groups.
  • alk ⁇ xy refers to alkyl-O-, wherein alkyl is defined herein above.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, te/t-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like.
  • alkoxy groups have about 1-7, more preferably about 1-4 carbons.
  • cycloalkyl refers to saturated or unsaturated but non- aromatic monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, preferably 3-8, or 3-7 carbon atoms. For bicydic, and tricyclic cycloaikyt system, all rings are non-aromatic.
  • exemplary monocyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyciopentyl, cyclopentenyl, cycfohexyl and cyclohexenyf.
  • Exemplary bfcyclic hydrocarbon groups include b ⁇ rnyl, decahydronaphthyl, bicyclo(2.1.1Jhexyl, bicyclo ⁇ 2.2.1]heptyl, bicyclof2.2.1]heptenyl, bicyclo[2.2.2]octyl.
  • Exemplary tricyclic hydrocarbon groups include adamantyl.
  • C 3 . 7 cycloakyr refers to a cyclic hydrocarbon groups having 3 to 7 carbon atoms.
  • cycloaikylalkyl refers to an alkyl susbtituted with cycloalkyl
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-10 carbon atoms in the ring portion.
  • aryl also refer to a group in which the aromatic ring is fused to a cycloalkyl ring, where the radical of attachment is on the aromatic ring or on the fused cycloalkyt ring Representative examples of aryi are phenyl, naphthyl, hexahydroindyl, indanyl or tetrahydronaphthyl
  • C 6 l oaryl refers to an aromatic hydrocarbon groups having 6 to 10 carbon atoms in the ring portion
  • arylalkyl is an aikyl substituted with aryl.
  • Representative examples of arylalkyl are benzyl or Phenyl-CH 2 CH ? - The term also includes substituted arylalkyl moiety
  • Heteroaryr includes monocyclic or bicyclic heteroaryl. containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms and each heteroatoms is indepdendently selected from O, N or S wherein S and N may be oxidized to va ⁇ ous oxidation states.
  • the system is fully aromatic ( ⁇ e. al! rings are aromatic).
  • Typical monocyclic heteroaryl groups include thienyl, furyl, pyrrolyl, imtdazojyl, pyrazolyl, thiazolyl, isothiazotyl, oxa-2,3-diazolyl, oxa-2,4-diazolyl, oxa-2.5-d ⁇ azolyl, oxa-3,4- diazolyl, th ⁇ a-2,3-diazofyl, th ⁇ a-2,4-diazolyl, th ⁇ a-2,5-diazolyl, th ⁇ a-3,4-d ⁇ azolyl, 3-, A-, or 5- tsothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazoiyl, 3- or 5-1 ,2,4-tr ⁇ azolyl, 4- or 5-1 ,2, 3- triazolyl, tetrazolyl, 2 ⁇ , 3-, or 4-pyr ⁇ dy
  • heteroaryl also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyi rings, where the radical or potnt of attachment is on the heteroaromatic ring or on the fused aryl rmg.
  • bicydic heteroaryl are indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, quinolizinyl, quinoliny ⁇ , isoquinoKnyl, cinnolinyl, phthalaztny!, naphthyridinyl, quinazolmyl, quinaxalinyl, th ⁇ eno ⁇ 2,3-b]furanyl, furo ⁇ 3,2-b]-pyranyl, ⁇ H-pyrido ⁇ -dJ-o-oxazinyl, 1H-pyrazoJo[4,3-d]- oxazolyl, 4H-tm ⁇ dazo ⁇ 4 > 5-d] thiazolyl, pyraz ⁇ no[2,3-d]py ⁇ dazinyl, im ⁇ dazo ⁇ 2 1-b] thiazoiyl, im ⁇ dazo[1,2-b][1 ,2,4]tr ⁇ az
  • heterocyclyl or “heterocydo” refers to an optionally substituted, saturated or unsaturated non-aromatic (partially unsaturated) ring which is a 4-, 5-, 6-, or 7-membered monocyclic, and contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states.
  • a non-aromatic ring system is defined as being a non-fully or partially unsaturated ring system.
  • bicyclic and tricyclic heterocyclyl ring systems includes heterocyclyl ring systems wherein one of the fused rings is aromatic but the other(s) is (are) non-aromatic.
  • heterocyclyl moiety represents a saturated monocyclic ring containing from 5-7 ring atoms and optionally containing a further heteroatom, selected from O, S or N.
  • the heterocyclic group can be attached at a heteroatom or a carbon atom.
  • the heterocyclyl can include fused or bridged rings as well as spirocyclic rings.
  • heterocycles include dihydrofuranyf, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithioiane, oxathianyl, thiomorpholino, oxirany), aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, piperazinyl, azepinyl, oxapinyl, oxaazepanyl, oxathianyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl.
  • hydroxyalkyl refers to alkyl groups, as decrtbed above, in which the afkyl group is substituted with one or more hydroxy.
  • halogen includes fluorine, bromine, chlorine and iodine.
  • perhalogenated generally refers to a moiety wherein ail hydrogens are replaced by halogen atoms.
  • heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. In another embodiment, the heteroatom is nitrogen, oxygen or sulfur-
  • the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemical ⁇ controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application afso include ail tautomers thereof.
  • the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers” are a pair of stereoisomers that are non- superimposabie mirror images of each other.
  • a 1 : 1 mixture of a pair of enantiomers is a "racemtc" mixture.
  • the term is used to designate a racemic mixture where appropriate.
  • "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S, Resolved compounds whose absolute configuration is unknown can be designated (+) of (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycioalkyl, the cycloalkyl substituent may have a cis- or transconfiguration. All tautomeric forms are also intended to be included.
  • any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R 1 S)- configuration.
  • each asymmetric atom has at least 50 % enantiomerlc excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration.
  • Substituents at atoms with unsaturated bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.
  • a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optica! isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyf tartaric acid, di-O,O'-p-to1uoyi tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic products can also be resolved by chJral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • the term "pharmaceutically acceptable salts 1' refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which are not biologically or otherwise undesirable.
  • the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edtsylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsuiphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate.
  • inorganic acids and organic acids e.g., acetate, aspartate, benzoate, besylate, bicarbonate/carbonate
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycoiic acid, pyruvic acid, oxalic acid, maleic acid, rnalonic acid, succinic acid, f ⁇ maric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesuifonic acid, ethanesulfonic acid, p ⁇ toluenesulfonic acid, salicylic acid, and the like.
  • inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived inciude for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropyiamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanoiamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na 1 Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na 1 Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • any hydrogen represented by "H” in any of the formulae herein is intended to represent all tsotoptc forms of hydrogen (e.g. 1 H, 2 H or D, 3 H);
  • any carbon represented by "C” in any of the formulae herein is intended to represent all isotopic forms of carbon (e.g. 11 C, 13 C, 14 C);
  • any nitrogen represented by "N” is intended to represent all isotopic forms of nitrogen (e.g. 14 N, 16 N).
  • isotopes that are included in the invention include isotopes of oxygen, sulfur, phosphorous, fluorine, iodine and chlorine, such as 18 F 31 P, 32 P, 35 S 1 38 CI, 125 I.
  • the invention includes vartous isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 13 C, and 14 C are present.
  • the atoms in the formulae herein occur in their natural abundance.
  • one or more hydrogen atom may be enriched in 2 H; or/and one or more carbon atom may be enriched in 11 C 1 13 C or 14 C; or/and one or more nitrogen may be enriched in 14 N.
  • Such isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopicafly labeled reagent.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at ieast 4000 (60% deuterium incorporation), at ieast 4500 (67.5% deuterium incorporation), at ieast 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at ieast 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • Isotopically-enriched compounds of formulae I' or I to VIIC can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-enriched reagent in place of the non-enriched reagent previously employed
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d ⁇ -acetone, d ⁇ -DMSO.
  • Compounds of the invention i.e. compounds accroding to anyone of formulae I' and I to VIIC, that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
  • These co- crystals may be prepared from compounds according to anyone of formulae !' and I to VIIC by known co-crystal forming procedures. Such procedures include grinding, heating, co- subliming, co-melting, or contacting in solution compounds according to anyone of formulae I' and I to VIiC with the co-crystal former under crystallization conditions and isolating co- crystals thereby formed.
  • Suitable co-crystal formers include those described in WO 2004/078163.
  • the invention further provides co-crystals comprising a compound according to anyone of formulae I' and I to VIIC.
  • the term "pharmaceutically acceptable carrier” includes any and ail solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example. Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • the term "a therapeutically effective amount' refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by neutral endopeptidase EC 3.4. 24.11 or (ii) associated with neutral endopeptidase EC 3.4.
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-ordinateiular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of neutral endopeptidase EC 3.4. 24.11; or at least partially reducing or inhibiting the expression of neutral endopeptidase EC 3.4. 24.11.
  • the term "subject" refers to an animal.
  • the animal is a mammal.
  • a subject also refers to for example, primates ⁇ e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • the subject is a human.
  • the term “inhibition” or “inhibiting 0 refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • treating refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • treating refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • treating or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • hypertension refers to a condition where the pressure of blood within the blood vessels is higher than normal as it circulates through the body, When the systolic pressure exceeds 150 mmHg or the diastolic pressure exceeds 90 mmHg for a sustained period of time, damage is done to the body. For example, excessive systolic pressure can rupture blood vessels anywhere, and when it occurs within the brain, a stroke results. Hypertension may also cause thickening and narrowing of the blood vessels which ultimately could lead to atherosclerosis.
  • type 2 diabetes including type 2 diabetes associated with hypertension refers to a disease in which the pancreas does not secrete sufficient insulin due to an impairment of pancreatic beta-cell function and/or in which there is to insensitivity to produced insulin (insulin resistance).
  • the fasting plasma glucose is less than 126 mg/dL
  • pre-diabetes is, e.g., a condition which is characterized by one of following conditions: impaired fasting glucose ⁇ 110-125 mg/dL) and impaired glucose tolerance (fasting glucose levels less than 126 mg/dL and post-prandial glucose level between 140 mg/dL and 199 mg/dL).
  • Type 2 diabetes meliitus can be associated with or without hypertension.
  • Diabetes meliitus occurs frequently, e.g., in African American, Latino/Hispanic American, Native American, Native American, Asian American and Pacific Islanders. Markers of insulin resistance include HbAIC, HOMA IR, measuring collagen fragments, TGF- ⁇ in urine, PAI-1 and prorenin.
  • the compounds of the present invention may also form interna) salts, e.g., zwitterionic molecules.
  • the present invention also provides pro-drugs of the compounds of the present invention that converts in vivo to the compounds of the present invention.
  • a pro-drug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject.
  • the suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art.
  • Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego. Calif., 2001).
  • bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
  • Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve ⁇ ptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety Is acceptably non-toxic.
  • Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased iipophHicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property).
  • IipophHicity can be increased by esteriftcation of (a) hydroxy!
  • carboxyltc acids e.g., a carboxylic acid having at least one lipophilic moiety
  • carboxylic add groups with lipophilic alcohols e.g., an alcohol having at least one lipophilic moiety, for example aliphatic alcohols.
  • Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has a meaning as defined herein.
  • Preferred are pharmaceutically acceptable ester derivatives convertible by soivojysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or dt-substiiuted lower aikyl esters, such as the ⁇ -(amino, mono- or di-iower alkylamino, carboxy, lower alkoxycarbonyl)- lower alkyl esters, the ⁇ -(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-fower alkyl esters, such as the pivaloyloxymethy
  • the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds of the invention can be synthesized using the methods described in the following schemes, examples, and by using art recognized techniques. All compounds described herein are included in the invention as compounds. Compounds of the invention may be synthesized according to at least one of the methods described in schemes 1 -4.
  • protecting group a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention.
  • the protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W, McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999.
  • Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se.
  • salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used.
  • metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid
  • organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium
  • Acid addition salts of compounds of the present invention are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent.
  • Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.
  • Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
  • diastereoisomers can be separated in a manner known per se into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by e.g. medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisorners so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.
  • Intermediates and final products can be worked up and/or purified according to standard methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like.
  • All the above-mentioned process steps can be carried out under reaction conditions that are known per se, including those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, including, for example, solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g.
  • mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described under "Additional process steps”.
  • solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethytformamtde or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or t ⁇ -methylpyrrolidin-2- one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example
  • the compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
  • the invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
  • the compounds of the invention of formula Il can be prepared by hydrolysis of intermediates A to C wherein X 1 X 1 , A 1 , R 1 , R 2 and n have the definition of Formula I or I', supra; and P 1 and P 2 are appropriate protecting groups selected from, but not limited to, methyl, ethyl, isopropyl, tert-butyl, methoxybenzyl or benzyl.
  • Intermediate C The compounds of the invention of formula IM can be prepared by hydrolysis of intermediate D, E or F wherein X, X 1 , A 1 , R 1 , R 2 and n have the definition of Formula I or I', supra, and P 1 and P 2 can be appropriate protecting groups selected from, but not limited to, methyl, ethyl, isopropyl, tert-butyl. methoxybenzyi or benzyl.
  • the compounds of the invention of formula VII can be prepared by hydrolysis of intermediate G wherein A 2 , R 1 , R 2 , R 4 and n have the definition of Formula I or )', supra, and P 1 can be appropriate protecting group selected from, but not limited to, methyl, ethyl, isopropyl, tert- butyl, methoxybenzyi or benzyl.
  • Standard methods can be applied for the hydrolysis of lntermeidates A to G using a base selected from, but not limited to, NaOH, KOH or LiOH. or an acid selected from, but not ltmited to, TFA or HCt.
  • a base selected from, but not limited to, NaOH, KOH or LiOH. or an acid selected from, but not ltmited to, TFA or HCt.
  • P 1 or P 3 is benzyl or methoxybenzyl
  • preferable method of deprotection is hydrogenation in the presence of a catalyst such as, but not limited to, palladium-on-carbon under hydrogen.
  • the intermediate A, B, C or G can be prepared using the following process comprising; condensing an intermediate H or I wherein X 1 P ⁇ R 1 , R 2 and n are as previously described:
  • condensation methods may be applied including, but not limited to, conversion of the intermediate J, K or L to their corresponding acid halide, using reagents such as thiony) chloride or oxalyl chloride, or conversion of intermediate J, K or L to mixed anhydride using reagents such as CIC(O)O-isobutyl or 2 ,4,6-irichlorobenzoyi chloride followed by reaction of the acid halide or mixed anhydride with the intermediate H or I in a presence or absence of a base such as tertiary amine (e.g. triethylamine, DIPEA 1 or N « methylmorpholine) or pyridine derivative (e.g.
  • a base such as tertiary amine (e.g. triethylamine, DIPEA 1 or N « methylmorpholine) or pyridine derivative (e.g.
  • the intermediate J, K, or L can be coupled with H or I using coupling reagents such as DCC, EDCI, PyBOP or BOP in presence or absence of a reagent such as 1- hydroxybenazotriazole, 1-hydroxy-7-azabenzotriazole or pe ⁇ tafluorophenoi.
  • coupling reagents such as DCC, EDCI, PyBOP or BOP in presence or absence of a reagent such as 1- hydroxybenazotriazole, 1-hydroxy-7-azabenzotriazole or pe ⁇ tafluorophenoi.
  • step 1a intermediate I is reacted with an appropriate carboxylic acid using standard coupling reagents selected from, but not limited to, DCC, EDCI, PyBOP or BOP in presence or absence of a reagent such as 1-hydroxybenazotriazole, 1-hydroxy-7-azabenzotriazole or pentafluorophenol; follwoed by removal of P 2 protecting group in step 1c using a base selected from, but not limited to, NaOH, KOH or LiOH, or an acid selected from, but not limited to, TFA or HCI, or hydrogenation with a catalyst such as, but not limited to, palladium- on-carbon under hydrogen.
  • standard coupling reagents selected from, but not limited to, DCC, EDCI, PyBOP or BOP in presence or absence of a reagent such as 1-hydroxybenazotriazole, 1-hydroxy-7-azabenzotriazole or pentafluorophenol
  • a base selected from, but not limited to, NaOH, KOH or Li
  • intermediate I is reacted with an appropriate anhydride in the presence of a base selected from, but not limited to, pyridine, triethylamine or diisopropylethylamine (step 1b); followed by conversion of the carboxylic acid into a tetrazole (step 1b) using similar method as described in Journal of Medicinal Chemistry 1998, 41 , 1513.
  • a base selected from, but not limited to, pyridine, triethylamine or diisopropylethylamine
  • the intermediate D, E or F can be prepared using the following process comprising: condensing an intermediate M wherein X 1 P 1 , R 1 , R 2 and n are as defined above;
  • condensation methods may be applied including, but not limited to, conversion of the intermediate M or N to acid halide, using reagents such as thionyl chloride or oxalyl chloride, or conversion of intermediate M or N to mixed anhydride using reagents such as CIC(O)O-isobutyl or 2,4.6-trichlorobenzoyl chloride followed by reaction of the acid chloride or mixed anhydride with the intermediate Q or S in a presence or absence of a base such as tertiary amine (e.g. triethylamine, DIPEA, or N-methylmorphoitne) or pyridine derivative (e.g. pyridine.
  • a base such as tertiary amine (e.g. triethylamine, DIPEA, or N-methylmorphoitne) or pyridine derivative (e.g. pyridine.
  • the intermediate M or N can be coupled with the intermediate Q or S using a reagent such as DCC, EDCl, PyBOP or BOP in presence or absence of a reagent such as 1 ⁇ hydroxybenazotriazole, 1- hydroxy-7-azabenzotriazole or pentafluorophenol.
  • a reagent such as DCC, EDCl, PyBOP or BOP in presence or absence of a reagent such as 1 ⁇ hydroxybenazotriazole, 1- hydroxy-7-azabenzotriazole or pentafluorophenol.
  • P 1 is a protecting group selected from, but not limited to, hydrogen, methyl, ethyl, propyl, t ⁇ rf-butyl, methoxymethyl, tert-butyldimethylsilyi, tetrahydrofuranyl, benzyl, ally) or phenyl;
  • R 5 is for example hydrogen, methyl, ethyl, isopropyl, benzyl or phenyl;
  • R 6 and R 7 are independently hydrogen, methyl, ethyl, isopropyl, benzyl or phenyl.
  • Y is selected from, but not limited to, chloro, bromo, iodo, benzotriazoloxy, pyridinium, N, ⁇ klimethylaminopyridinium, pentafluorophenoxy, phenoxy, 4-chlorophenoxy, -OCO 2 Me, -OCO ⁇ Et, tert-butoxycarbonyi or ⁇ OCC(O)O-isobutyl.
  • step (2a) standard methods can be applied to prepare the corresponding acid halide, such as the use of thionyl chloride, oxalyl chloride; or standard methods to prepare the mixed anhydride or the acyl pyridinium cation can be applied, such as the use of pivaloyl chloride with a tertiary amine (e.g. triethylamtne, DIPEA, N-methylmorpho ⁇ ne) in the presence or absence of a pyridine derivative (e.g.
  • pyridine 4-(dimethylamino)pyridtne, 4- pyrroJidinopyridine), 2,4,6-trichlorobenzoyl chloride with a tertiary amine (e,g, triethylamine, DIPEA, W-methylmorphoHne) in the presence or absence of a pyridine derivative (e.g. pyridine, 4-(dimethylamino)pyridine, 4-pyrrolidinopyridine), or CiC(O)O-Z-Bu with a tertiary amine (e.g. triethylamine, DIPEA. N-methylmorpholine) tn the presence or absence of a pyridine derivative (e.g.
  • pyridine 4-(dimethylamino)pyridine, 4-pyrrolidinopyrtdine); or standard methods to prepare the activated ester can be applied, such as the use of 1- hydroxybenazotriazole, 1-hydroxy-7-azabenzotriazole or pentafluorophenol in the presence of a coupling reagent (e.g. DCC 1 EDCI) or BOP.
  • a coupling reagent e.g. DCC 1 EDCI
  • BOP e.g. DCC 1 EDCI
  • step (2c) Standard methods for alkylation can be employed. An illustrative example is outlined in Chemical Reviews 1996, 96(2), 835 - 876 and the references therein.
  • step (2d) standard methods for cleavage of N-acyloxazoHdinone or N-acyloxaztnanone can be employed. Illustrative examples of this chemistry are outlined in Aldrichchimica Acta 1997, Vo. 30, pp. 3 - 12 and the references therein.
  • R 1 , R 2 , X and n are as defined above and wherein P 3 is a protecting group selected from, but not limited to, te/t-butyt, benzyl, t ⁇ phenylphosphynyl, tert-b ⁇ toxycarbonyl, benzyloxycarbonyl, ailyloxycarbonyl, acetyl or trifluoroacetyl.
  • step (3a) standard methods for introduction of the amine part can be employed, such as using: either simultaneous treatment with or stepwise treatment via the corresponding acyl azide formation by using thionyl chloride (or CICO 2 R 8 ), NaN 3 (or TIvISN 3 ) and R 8 OH ⁇ wherein R 6 and R 9 are hydrogen, methyl, ethyl, tert-butyl, allyl, benzyl or 4-methoxybenzyl); or either simultaneous treatment with or stepwise treatment via the corresponding acyl azide formation with DPPA and R 9 OH (wherein R 9 is defined as above); or standard methods for conversion to the corresponding carboxamide followed by treatment with NH 3 equivalent and either simultaneous treatment with or stepwise treatment with LTA or hypervalent iodine reagents (e.g.
  • step (3b) standard methods for removing P 3 protecting groups can be applied, such as base hydrolysis using NaOH 1 KOH, or LiOH, acid hydrolysis using TFA or HCl, or hydrogenation using palladium-on-carbon under hydrogen.
  • LG is a leaving group selected from, but not limited to, Cl, Br 1 1, OMs, OTs or OTf.
  • step (4a) standard methods for Arndt-Eistert homologation can be employed. An illustrative example of this chemistry is outlined in ⁇ nantioselective synthesis of ⁇ -amino acids, T ⁇ Edition", John Wiley and Sons, Inc., NJ (2005), either directly or analogously.
  • step (4b) standard methods for afkylation can be employed, such as using R 1 LG in the presence of a base such as LDA, NHMOS, LHMDS or KHMDS
  • step (4c) standard methods to protect the carboxylic a ⁇ d can be employed, such as using TMSCHN 2 (for methyl ester), P'LG/base (e.g K 2 CO 3 , NaHCO 3 , Cs 2 CO 3 or K 3 PO 4 ), thionyl chloride (or oxalyl chlor ⁇ de)/R s OH, DCC(Or EDCI)/DMAP/R 9 OH, BOP/R 9 OK (or
  • step (Ad) standard methods for Suzuki coupling reaction can be applied, such as using a palladium (or nickel) species [e g Pd(PPh 3 ).), PdCI ? (dppf), Pd(OAc) s /a phosphine (e g PPh 3 , dppf, PCy 3 , P(tBu) 3 , XPhos), PaIC 1 Pd 2 (dba)j/ a phosphine (e g PPh 3 , dppf, PCy 3 , P(tBu) 3>
  • a base e g KF, CsF,
  • K 3 PO 4 Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH 1 KOH, NaO-f-Bu, KO-Z-Bu), and (R 2 )n-PhB(OH) 2 [or
  • step (4e) standard methods for removing P 3 protecting groups can be applied, such as base hydrolysis using NaOH, KOH, or LiOH, acid hydrolysis using TFA or HCI, or hydrogenation using palladium-on-carbon under hydrogen
  • the intermediate H or I may be prepared be following the synthetic routes outlined in Tetrahedron Letters, 2008, VoI 49, No. 33, pp 4977-4980 either directly or analogously and converting the obtained boronic actd into a substituted biphenyl by methods outlined in Organic Letters, 2002, Vol. 4, No. 22, pp 3803 - 3805
  • the intermediate H or I may be prepared be following the synthetic routes outlined in Tetrahedron. Asymmetry, 2006, VoI 17, No. 2, pp 205-209 either directly or analogously
  • the intermediate H or I may be prepared by methods of Mannich reaction
  • Illustrative examples of this chemistry are outlined in "Enantioselective synthesis of ⁇ -amino a ⁇ ds, 2 na Edition", John Wiley and Sons, inc., NJ (2005), either directly or analogously
  • the intermediate H or I may be prepared by enolate addition
  • Illustrative examples of this chemistry are outlined in "Enantioselective synthesis of ⁇ -amino acids, 2 nd Edition", John Wiley and Sons, Inc., NJ (2005), either directly or analogously
  • the intermediate H or I may be prepared by methods of aza-Michael reaction.
  • Illustrative examples of this chemistry are outlined in ⁇ nantiosetective synthesis of ⁇ -amino acids, 2 ⁇ ct Edition", John Wiley and Sons, Inc., NJ (2005), either directly or analogously.
  • the intermediate H or I may be prepared following the synthetic route outlined in Synlett, 2006, No. 4, pp, 539-542, either directly or analogously.
  • the invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition can be formulated for particufar routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
  • the pharmaceutical compositions of the present invention can be made up in a solid form including capsules, tablets, pills, granules, powders or suppositories, or in a liquid form including solutions, suspensions or emulsions.
  • compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as welt as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers etc.
  • the pharmaceutical compositions are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or poiyethylenegrycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, algintc acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersibte powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure andtor buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
  • compositions for transdermal application include an effective amount of a compound of the invention with carrier.
  • Carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayabte formulations, e.g., for delivery by aerosol or the like,
  • topical delivery systems will in particular be appropriate for dermal application. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
  • Such may contain sotubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a topical application may also pertain to an inhalation or to an intranasal application. They are conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
  • the present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g. , vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose.
  • agents which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
  • the compounds according to anyone of formulae I' and I to VIIC in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, e.g. neutral endopeptidase EC 3.4. 24.11 modulating properties, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
  • pharmacological properties e.g. neutral endopeptidase EC 3.4. 24.11 modulating properties, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
  • cardiovascular disorders such hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, cyclical oedema, Menieres disease, hyperaldosteroneism (primary and secondary) and hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-edampsia, endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovarian syndrome, implantation failure), asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition such
  • the present invention provides the use of a compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof.
  • the therapy is selected from a disease which is ameliorated by inhibition of neutral endopeptidase EC 3.4. 24.11.
  • the disease is selected from the afore-mentioned list, suitably hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure (including edema and salt retension), diabetic nephropathy, non- diabetic nephropathy, type-2 diabetis, and diabetic complications and most suitably cardiovascular disorders, such as hypertension, renal insufficiency including edema and congestive heart failure.
  • the invention provides a method of treating a disease which is ameliorated by the inhibition of neutral endopeptidase EC 3.4.
  • 24.11 comprising administration of a therapeutically acceptable amount of a compound according to anyone of formulae I', J 1 IA, II, HA, III, IHA, IV, IVA, V, VA, Vl, VIA and VII to VIIC, or a pharmaceutically acceptable salt thereof.
  • the disease is selected from the aforementioned list, suitably hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure (including edema and salt retension) ; diabetic nephropathy, non-diabetic nephropathy, type-2 diabetes, and diabetic complications and most suitably cardiovascular disorders, such as hypertension, renal insufficiency including edema and congestive heart failure.
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingred ⁇ ent(s) for a subject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • the above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds of the present invention can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenteral ⁇ , advantageously intravenously, e.g., as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 3 molar and 10 * ⁇ molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 rng/kg, or between about 1-100 mg/kg.
  • the activity of a compound according to the present invention can be assessed by the following in vitro & in vivo methods and/or by the following in vitro & in vivo methods well- described in the art. See A fluorescence lifetime-based assay for protease inhibitor profiling on human kallikrein 7 Doering K, Meder G, Hinnenberger M, Woelcke J, Mayr LM, Hassiepen U Biomol Screen. 2009 Jan; 14(1):1-9.
  • the in vitro inhibition of recombinant human neutral endopeptidase can be determined as follows:
  • Recombinant human neutral endopeptidase (expressed in insect cells and purified using standard methods, final concentration 7 pM) is pre-incubated with test compounds at various concentrations for 1 hour at room temperature in 10 mM sodium phosphate buffer at pH 7.4, containing 150 mM NaCI and 0.05 % (w/v) CHAPS.
  • the enzymatic reaction is started by the addition of a synthetic peptide substrate Cys(PT14)-Arg-Arg-Leu-Trp-OH to a final concentration of 0.7 ⁇ M.
  • Substrate hydrolysis leads to an increase fluorescence lifetime (FLT) of PT14 measured by the means of a FLT reader as described by Doering et al. (2009).
  • the effect of the compound on the enzymatic activity was determined after 1 hour (t ⁇ 60 min) incubation at room temperature.
  • the IC50 values corresponding to the inhibitor concentration showing 50% reduction of the FLT values measured in absence of inhibitor, are calculated from the plot of percentage of inhibition vs. inhibitor concentration using nonlinear regression analysis software.
  • the compound of the present invention may be administered either simultaneously with, or before or after, at least one other therapeutic agent.
  • the compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition.
  • the invention provides a product comprising a compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is the treatment of a disease or condition associated with neutral endopepttdase EC 3.4. 24.11 activity.
  • Products provided as a combined preparation include a composition comprising the compound of formulae I' and I to VIIC and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof, and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to anyone of formulae I' and I to VIIC 1 or a pharmaceutically acceptable salt thereof, and another therapeutic agent(s).
  • the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound according to anyone of formulae I 1 and I to VIIC 1 or a pharmaceutically acceptable salt thereof.
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the invention typically comprises directions for administration.
  • the compound of the invention, or a pharmaceutically acceptable salt thereof and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers.
  • the compound of the invention, or a pharmaceutically acceptable salt thereof, and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
  • the invention provides the use of a compound according to anyone of formulae !' and I to VIIC 1 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11. activity, wherein the medicament is prepared for administration with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent in the manufacture of medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11. activity, wherein the medicament is prepared for administration with a compound according to anyone of formulae f and I to VIIC 1 or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound according to anyone of formulae I 1 and I to VtIC, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11 activity, wherein the compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof, is prepared for administration with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11 activity, wherein the other therapeutic agent is prepared for administration with a compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11 activity, wherein the compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof, is administered with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11 activity, wherein the other therapeutic agent is administered with a compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof.
  • the invention also provides the use of a compound according to anyone of formulae !' and I to VIIC, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11 activity, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent in the manufacture of a medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11 activity, wherein the patient has previously (e.g. within 24 hours) been treated with a compound according to anyone of formulae I' and I to VlIC, or a pharmaceutically acceptable salt thereof.
  • the other therapeutic agent is selected from: HMG-Co-A reductase inhibitor, an angiotensin receptor blocker (ARBs, angiotensin M receptor antagonist), angiotensin converting enzyme (ACE) Inhibitor, a calcium channel blocker (CCB) 1 an endothelin antagonist, a renin inhibitor, a diuretic, an ApoA-l mimic, an antidiabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, an aldosterone synthase inhibitors (ASI), a CETP inhibitor or a phophodiesterase type 5 (PDE5) inhibitor.
  • HMG-Co-A reductase inhibitor an angiotensin receptor blocker (ARBs, angiotensin M receptor antagonist), angiotensin converting enzyme (ACE) Inhibitor
  • a calcium channel blocker (CCB) 1 an endothelin antagonist
  • a renin inhibitor a
  • combination with a second agent or treatment includes co-administration of the compound of the invention (e.g., a compound of Formulae I' or l-VltC or a compound otherwise described herein) with the second agent or treatment, administration of the compound of the invention first, followed by the second agent or treatment and administration of the second agent or treatment first, foliowed by the compound of the invention.
  • the compound of the invention e.g., a compound of Formulae I' or l-VltC or a compound otherwise described herein
  • second agent includes any agent which is known in the art to treat, prevent, or reduce the symptoms of a disease or disorder described herein, e.g .a disorder or disease responsive to the inhibition of neutral endopeptidase, such as for example, hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD).
  • neutral endopeptidase such as for example, hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hyper
  • endothelial dysfunction diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis.atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD), pulmonary arterial hypertension, renal failure (including edema and salt retension), cyclical oedema, Menieres disease, hyperaldosteroneism (primary and secondary) and hypercalciuria. ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia.
  • endometriosis, and reproductive disorders especially mate and female infertility, polycystic ovarian syndrome, implantation failure
  • asthma obstructive sleep apnea
  • inflammation leukemia
  • pain epilepsy
  • affective disorders such as depression and psychotic condition such as dementia and geriatric confusion, obesity and gastrointestinal disorders ⁇ especially diarrhea and irritable bowel syndrome
  • wound healing especiatly diabetic and venous ulcers and pressure sores
  • septic shock gastric acid secretion dysfunction
  • hyperreninaemia cystic fibrosis
  • restenosis type-2 diabetes
  • metabolic syndrome diabetic complications and atherosclerosis
  • second agents examples include HMG-Co-A reductase inhibitors, angiotensin Il receptor antagonists, angiotensin converting enzyme (ACE) Inhibitors, calcium channel blockers (CCB), endothelin antagonists, renin inhibitors, diuretics, ApoA-l mimics, antidiabetic agents, obesity-reducing agents, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase inhibitors (ASI) and CETP inhibitors.
  • HMG-Co-A reductase inhibitors examples include HMG-Co-A reductase inhibitors, angiotensin Il receptor antagonists, angiotensin converting enzyme (ACE) Inhibitors, calcium channel blockers (CCB), endothelin antagonists, renin inhibitors, diuretics, ApoA-l mimics, antidiabetic agents, obesity-reducing agents, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synth
  • HMG-Co-A reductase inhibitor also called beta-hydroxy-beta- methylglutaryl-co-enzyme-A reductase inhibitors
  • active agents that may be used to lower the lipid levels including cholesterol in blood. Examples include atorvastatin, cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin, ffuvastatin, lovastatin, pravastatin, mevastatin, pravastatin, rivastatin, simvastatin, and velostatin, or, pharmaceutically acceptable salts thereof.
  • ACE-inhibitor also called angiotensin converting enzyme inhibitors
  • ACE-inhibitor includes molecules that interrupt the enzymatic degradation of angiotensin I to angiotensin II. Such compounds may be used for the regulation of blood pressure and for the treatment of congestive heart failure. Examples include alacepril, benazepril, benazeprilat, captopril. ceronapril, cilazapril, delapril, enalapril, enaprifat, fosinoprii, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril. and trandolap ⁇ l, or, pharmaceutically acceptables salt thereof.
  • endothelin antagonist includes bosentan (cf . EP 526708 A), tezosentan (cf. WO 96/19459), or, pharmaceutically acceptable salts thereof.
  • renin inhibitor includes ditekiren (chemical name: [1 S- ⁇ 1 R*, 2FTAFT(I fl * ,2R * )])-H(1.1 -dimethylethoxy)carbonyl)-L-proly l-L-phenyfalanyl-N-[2- hydroxy-5 ⁇ methyl-1 -(2-methylpropyl)-4-[[[2-methyl-1 -[[(2- pyridinylmrthyl)aminoJcarbonyl]butyl]amino]carbonyl ⁇ hexyl3-N-aJfa-methyl-L-histidinamide); terlakiren (chemical name: [R-(f?* l S*)]-N-(4-morpholinylcarbonyl)-L-phenylalany!-N-[1- (cyclohexylmethyO ⁇ -hydroxy-S ⁇ I-methylethoxy ⁇ S-oxopropytJ-S-methyl
  • aliskiren if not defined specifically, is to be understood both as the free base and as a salt thereof, especially a pharmaceutically acceptable salt thereof, most preferably a hemi-fumarate salt thereof.
  • angiotensin Il receptor antagonist or a pharmaceutically acceptable salt thereof is understood to be an active ingredient which bind to the AT 1 -receptor subtype of angiotensin Il receptor but do not result in activation of the receptor.
  • these antagonists can, for example, be employed as antihypertensives or for treating congestive heart failure.
  • the class of ATi receptor antagonists comprises compounds having differing structural features, essentially preferred are the non-peptidic ones.
  • Preferred AT,-receptor antagonist are those agents which have been marketed, most preferred is valsartan or a pharmaceutically acceptable salt thereof.
  • calcium channel blocker includes dihydropyridines (DHPs) and non-DHPs (e.g., diftiazem-type and verapamil-type CCBs). Examples include amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, nig ⁇ ldipine, niludipine, ntmodipme, nisoldipine.
  • DHPs dihydropyridines
  • non-DHPs e.g., diftiazem-type and verapamil-type CCBs.
  • Examples include amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, nig ⁇ ldipine, niludipine, ntmodipme, nisoldipine.
  • nitrendipine, and nivaldipine and is preferably a non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil, or, pharmaceutically acceptable salts thereof.
  • CCBs may be used as anti-hypertensive, anti-angina pectoris, or anti-arrhythmic drugs.
  • diuretic includes thiazide derivatives (e.g.. chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorothalidon).
  • ApoA-l mimic includes D4F peptides (e.g., formula D-W-F-K-A-F-Y-D-K- V-A-E-K-F-K-E-A-F)
  • anti-diabetic agent includes insulin secretion enhancers that promote the secretion of insutin from pancreatic ⁇ -cells.
  • examples include biguanide derivatives (e.g., metformin), sulfonylureas (SU) (e.g., tolbutamide, chlorpropamide, tolazamide, acetohexamide, 4-chloro-N- ⁇ (1-pyrolidinylamino)carbonyl]-benzensulfonamide (glycopyramtde), glibenclamide (glyburide), gliclazide, 1-butyl-3-metanilylurea, carbutamide, glibonuride, glipizide, gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, and totylcyclamide), or pharmaceutically acceptable salts thereof.
  • phenylalanine derivatives e.g., nateglinide [N- (fr-ans ⁇ -isopropylcycl ⁇ h ⁇ xylcarbonyO-D-phenylaianine] (cf. EP 196222 and EP 526171) of the formula
  • DPP-IV is responsible for inactivating GLP-1. More particularly, DPP-IV generates a GLP-1 receptor antagonist and thereby shortens the physiological response to GLP-1, GLP- 1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal.
  • the DPP-IV inhibitor can be peptidic or, preferably, non-peptidic.
  • DPP-IV inhibitors are in each case generically and specifically disclosed e.g. in WO 98/19998, DE 196 16 486 A1, WO 00/34241 and WO 95/15309, in each case in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications.
  • Preferred are those compounds that are spectfically disclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241, respectively.
  • GLP-1 is an insulinotropic protein which is described, e.g., by W.E. Schmidt et al. in Diabetologia, 28, 1985, 704-707 and in US 5,705,483.
  • GLP-1 agonists includes variants and analogs of GLP-1 (7-36)NH 2 which are disclosed in particular in US 5,120,712, US 5,118666, US 5,512,549, WO 91/11457 and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826.
  • GLP-1(7- 37) in which compound the carboxy-terminal amide functionality of Arg 3 ⁇ is displaced with Gly at the 37 th position of the GLP-1 (7-36)NH 2 molecule and variants and analogs thereof including GLN 9 -GLP- 1(7-37), D-GLN*-GLP- 1(7-37), acetyl LYS 9 -GLP « 1(7-37), LYS 1 ⁇ -GLP- 1(7-37) and, in particular, GLP-1 (7-37)OH, VAL 8 -GLP ⁇ 1 (7-37), GLY 8 -GLP-1(7-37), THR 8 - GLP-1(7-37), MET ⁇ -GLP-I (7-37) and 4-imidazopropionyl ⁇ GLP ⁇ 1.
  • Special preference is also given to the GLP agonist analog exendin-4, described by Greig e( a/, in Diabetologia 1999, 42, 45-50.
  • insulin sensitivity enhancers which restore impaired insulin receptor function to reduce insulin resistance and consequently enhance the insulin sensitivity.
  • examples include hypoglycemic thiazolidinedio ⁇ e derivatives (e.g., glitazone, (SM(3,4-dihydr ⁇ -2-(phenyl-methy[)-2H-1- benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5- ⁇ f4-(3-(5 ⁇ methyl-2-phenyl-4- oxazolyl)-1 -oxopropy!)-phenylj ⁇ methyl ⁇ -thiazolidine-2,4-dk>ne (darglitazone), 5- ⁇ [4- ⁇ 1 -methyl- cyclohexyl)methoxy)-pheny ⁇ ]methyl ⁇ -thiazolidine-2,4-d ⁇ one (ciglUazone), 5- ⁇ [4- ⁇ 2-(1- indoly
  • insulin signalling pathway modulators like inhibitors of protein tyrosine phosphatases (PTPases), antidiabetic non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT); compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G ⁇ Pase), inhibitors of fructose-1,6-btsphosphatase (F-1,6-8pase), inhibitors of glycogen phosphorylase (GP) 1 glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxylase (PEPCK); pyruvate dehydrogenase kinase (PDHK) inhibitors; inhibitors of gastric emptylng; insulin; inhibitors of GSK-3; retinoid X receptor (RXR) agonists; agonists of Beta-3 AR; agonists of uncoupling proteins (UC)
  • PTPases protein ty
  • appetite-reducing agent includes lipase inhibitors (e.g. , oriistat) and appetite suppressants (e.g., sibutramine and phentermine).
  • lipase inhibitors e.g. , oriistat
  • appetite suppressants e.g., sibutramine and phentermine
  • aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof is understood to be an active ingredient that has the property to inhibit the production of aldosterone.
  • Aldosterone synthase (CYP11B2) is a mitochondrial cytochrome P450 enzyme catalyzing the last step of aldosterone production in the adrenal cortex, i.e., the conversion of 11 -deoxycorticosterone to aldosterone.
  • the inhibition of the aldosterone production with so-called aldosterone synthase inhibitors is known to be a successful variant to treatment of hypokalemia, hypertension, congestive heart failure, atrial fibrillation or renal failure.
  • Such aldosterone synthase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., US 2007/0049616).
  • the class of aldosterone synthase inhibitors comprises both steroidal and nonsteroidal aldosterone synthase inhibitors, the later being most preferred.
  • the class of aldosterone synthase inhibitors comprises compounds having differing structural features.
  • the most preferred non-steroidal aldosterone synthase inhibitor is the (+)-enantiomer of the hydrochloride of fadrozole (US patents 4617307 and 4889861) of formula
  • a preferred steroidal aldosterone antagonist is eplerenone (cf. EP 122232 A) of the formula
  • Aldosterone synthase inhibitors useful in said combination are compounds and analogs generically and specifically disclosed e.g. in US2007/0049816, in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to this publication.
  • Preferred aldosterone synthase inhibitors suitable for use in the present invention include, without limitation 4-(6,7-dihydro- ⁇ H-pyi ⁇ oiop ⁇ -climidazol-S-yO-S-methylbenzonitrile; 5-(2-chloro-4-cyanophenyl)-6,7-dthydro- 5H-pyrrolo[1 ⁇ -cjimfdazole- ⁇ -carboxylic acid (4-methoxybenzyl)methylamide; 4'-fluoro*6- (6.7,8,9-tetrahydro-5H-imidazo[1 ,5-a ⁇ azepin-5 ⁇ yl)bipnenyl-3-carbonitrile; 5-(4-Cyano-2- methoxyphenyO- ⁇ J-dihydro- ⁇ H-pyrroloti ⁇ -cJimidazole-S-carboxylic acid butyl ester, 4-(6,7- Dihydro-5H-pyrrolot1
  • aldosterone synthase inhibitors also include compounds and analogs disclosed in WO2008/076860, WO2008/076336, WO2008/076862, WO2008/027284, WO2004/046145, WO2004/014914, WO2001 /076574.
  • Aldosterone synthase inhibitors also include compounds and analogs disclosed in U.S. patent applications US2007/0225232, US2007/0208035, US2008/0318978, US2008/0076794, US2009/0012068, US20090048241 and in PCT applications WO2006/005726, WO2006/128853, WO2006128851 , WO2006/128852, WO2007065942, WO2007/116099, WO2007/116908, WO2008/119744 and in European patent application EP 1886695.
  • Preferred aldosterone synthase inhibitors suitable for use in the present invention include, without limitation 8-(4-Fluorophenyl)-5 l 6-dihydro-8H-imida2x>[5,1-c1(1 ,41oxazine; 4-(5,6-Dfhydr ⁇ -8H-imidazo(5,1-c][1 ,4]oxazin-8 ⁇ yl)-2-fluorobenzonitriie; 4-(5,6- Dihydro-8H-imidazo[5, 1 -c ⁇ (1 ,4Joxazin ⁇ 8-yl)-2,6-difluorobenzonitrile; 4 ⁇ (5,6-Dihydro-8H- imidazo[5,1-c)(1 ,4Joxazin-8-yl)-2-methoxybenzonitriie; 3-(5,6-Dihydro-8H-imidazo[5,1-c ⁇ [1 ,4
  • endothelin receptor blocker includes bosentan.
  • CETP inhibitor refers to a compound that inhibits the cholesteryl ester transfer protein (CETP) mediated transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL.
  • CETP inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., U.S. Pat. No. 6,140,343). Examples include compounds disclosed in U.S. Pat. No. 6,140,343 and U. S. Pat. No. 6,197,786 (e.g.
  • 6,723,752 e.g., (2R)-3- ⁇ 3-(4-Chloro-3-ethyl-phenoxy)-phenylH[3-(1 , 1 ,2,2- tetrafluoro-ethoxy)-phenyl]-methyl ⁇ -amino ⁇ - 1,1 ,1 -trifluoro-2-propanoO; compounds disclosed in U.S. patent application Ser. No. 10/807,838; polypeptide derivatives disclosed in U.S. Pat. No. 5,512,548; rosenonolactone derivatives and phosphate-containing analogs of cholesteryl ester disclosed in J. Antibiot, 49(8): 815- 816 (1996), and Bioorg. Med. Chem. Lett.; 6:1951-1954 (1996), respectively.
  • the CETP inhibitors also include those disclosed in WO2000/017165, WO2005/095409 and WO2005/097806.
  • a prefered PDE5 inhibitor is Sildenafil.
  • Second agent of particular interest include Endothelin antagonists, renin inhibitors, angiotensin Il receptor antagonists, calcium channel blockers, diuretics, antidiabetic agents such as DPPIV inhibitors, and aldosterone synthase inhibitors.
  • the obtained residue is purified by flash column chromatography on CN-modified silica gel (el ⁇ ent: heptane/EtOAc « 100:0 to 0:100) and by RP-HPLC (S ⁇ nFire C18, H 2 O(0.1%TFA)/CH 3 CN) to give (R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ytamino)-4- oxobutanoic acid (148.2 mg).
  • Example 1 «2: Synthesis of (RH ⁇ I ⁇ S' ⁇ hlorobiphenyM-yO ⁇ th ⁇ xy-A-oxobutan ⁇ - ylaminoM-ox ⁇ butanofc acid
  • Example 2-2 1H NMR (400 Mf-te, CHLOROFORM-d) ⁇ ppm 1.29 (t, J » 7 Hz, 3 H) 2.47 ⁇ 2.67 (m, 6 H) 2.84 - 3.02 (m. 2 H) 4.12 - 4.24 (m, 2 H) 4.47 - 4.55 (m, 1 H) 6.52 (br d, J * 9.3 Hz, 1 H) 7.24 - 7.26 (m, 2 H) 7.39 - 7.41 (m, 2 H) 7.48 - 7.51 (m, 4 H).
  • Example 2-4 1H NMR (400 MHz, CHLOROFORM-d) ⁇ ppm 1.28 (t, J - 7 Hz, 3 H) 2.44 - 2.65 (m, 6 H) 2.85 - 3.02 (m. 2 H) 3.67 (s, 3 H) 4.11 - 4.23 (m, 2 H) 4.48 - 4.56 (m, 1 H)
  • Example 2-6 1H NMR (400 MHz, CHLOROFORM-d) ⁇ ppm 1.28 (t, J « 7 Hz, 3 H) 2.44 -
  • Example 2-11 1H NMR (400 MHz, CHLOROFORM-d) ⁇ ppm 1.27 - 1.30 (m, 6 H) 2.44 -
  • Example 2-13 1H NMR (400 MHz, CHLOROFORM- ⁇ ⁇ ppm 1.29 (t, J - 7.2 Hz 1 3 H) 2.44 - 2,65 (m, 6 H) 2.86 - 2.91 (m, 1 H) 2.98 ⁇ 3.03 (m. 1 H) 3.67 (s, 3 H) 4,13 - 4.22 (m, 2 H) 4.47 - 4.56 (m.
  • Example 2-20 1H NMR (400 MHz 1 CHLOROFORM-c/) ⁇ ppm 1.28 (t, J - 7.2 Hz, 3 H) 1.43 (s, 9 H) 2.36 -2.56 (m, 6 H) 2 84 - 3.01 (m, 4 H) 4.11 - 4.22 (m, 2 H) 4.47 - 4.56 (m, 1 H) 6.30 - 6.35 (m, 1 H) 7.25 - 7.27 (m, 2 H) 7.51 - 7 .54 (m, 2 H).
  • Example 3-1 Syntheis of (R)»6-(1-(biphenyJ-4-yl) «4-ethoxy-4-oxobutan-2- ylcarbamoyl)pyrimidine-4-earboxyHc acid
  • Example 3-7 1H NMR (400 MHz, DMSO-d6) ⁇ ppm 1.13 (t, J - 7 Hz, 3 H) 2.56 - 2.58 (m, 2 H) 2,83- 2.94 (m, 2 H) 4.02 (q, J « 7 Hz, 2 H) 4.46 - 4.55 (m, 1 H) 7.19 (s, 2 H) 7.30 - 7.35 (m. 3 H) 7.42 - 7.46 (m ,2 H) 7.58 - 7.65 (m, 4H) 8.22 (d. J * 8.1 Hz, 1 H) 8.60 (s, 1 H).
  • Example 3-16 1H NMR (400 MHz, CHLOROFORM-d) ⁇ ppm 1,24 (t, J ⁇ 7.1 Hz 1 3 H) 2.38 - 2.42 (m. 2 H) 2.49 - 2.61 (m, 4 H) 2.82 - 3.00 (m, 2 H) 4.12 (q.
  • Example 3-27 1H NMR (400 MHz, CHLOROFORM-d) ⁇ ppm 2.07 (quint, J * 7.4 Hz, 2 H) 2.51 - 2.63 (m, 4 H) 2.82 - 3.02 (m, 8 H) 4,50 - 4.59 (m, 1 H) 6.28 (d, J ⁇ 8.6 Hz, 1 H) 6.78 - 6.81 (m, 1 H) 6.91 (d, J - 1.8 Hz, 1 H) 7.26 - 7.36 (m, 6 H) 7.41 - 7.44 (m, 1 H) 7.47 - 7.50 (m, 2 H) 7.53 - 7.54 (m, 1 H).
  • Example 3*29 Synthesis of (R) ⁇ 3 «(4 ⁇ benzyloxy)-4-oxobutan-smido ⁇
  • Example 4-1 Synthesis of (R)-4-biphenyi-4-yl-3- ⁇ 2-1H-tetrazol-5-yl-acetylamino)- butyric acid ethyl ester
  • Example 4-15 Synthesis of 5-[(R)-1-(3''Chloro-biphenyl-4-ylmethyl)-2 ⁇ ethoxycarbonyl- ethylcarbamoyO-1 H-pyrazole-3-carboxyUc acid
  • Example 4-20 (R)-3-t(5-Carboxymethyf-furan'2-carbonyl)-aminoJ-4-(3 1 >chloro-biphenyl- 4-yl)-butyric acid ethyl ester and
  • Example 4-21 (R)-3 «[(5-Carboxymethy!-f uran-2-carbonyJ)-aminoI-4-(3'-chJoro-biphenyl- 4-yi) ⁇ butyric acid
  • Example 5-7 1H NMR (400 MHz, CD3OD) ⁇ ppm 2.40-2.52 (m, 6 H) 2.83 - 2.92 (m, 2 H) 3.77 (s, 3 H) 4.44 - 4.47 (m, 1 H) 6.96 - 7.05 (m, 2 H) 7.23 - 7.30 (m, 4 H) 7.39 -7.41 (m, 2 H)
  • Example 5-8 1H NMR (400 MHz, CD300) ⁇ ppm 2.21 (s, 3 H) 2.41-2.55 (m, 6 H) 2.82 - 2.94 (m, 2 H) 3.77 (s, 3 H) 4.45 - 4.48 (m, 1 H) 7.15 - 7.28 (m, 8 H)
  • Example 5-12 1H NMR (400 MHz, DMSO-d ⁇ ) ⁇ ppm 2.54 - 2.70 (m, 2 H), 2.88 - 3.03 (m, 2 H) 1 4.56 - 4.65 (m, 1 H), 7.29 - 7.34(m, 3 H). 7.41 - 7.45 (m, 2 H), 7.55 - 7.63 (m, 4 H), 8.33 (s, 1 H), 9.15 (d, J « 9.1 Hz, 1 H) 1 9.49 (s. 1 H) 1 12,30 (br s, 1 H), 14.11 ⁇ br s, 1 H).
  • Example 5-13 1 H NMR (400 MHz 1 CD3OD) 6 ppm 2.38 - 2.57 (m. 6 H) 2.87 (A of ABX 1 Jab
  • Example 5-24 1H NMR (400 MHz, DMSO-d6) ⁇ ppm 2.50 - 2.61 (m, 2 H) 2.83 - 2,94 (m. 2 H) 4.43 - 4.52 (m, 1 H) 6.82 (s, 1 H) 7.28 - 7.35 (m, 3 H) 7.44 (t, J * 7.7 Hz, 2 H) 7.58 - 7.65 (m, 4 H) 8.12 (s, 1 H) 8.86 (d, J - 8 3 Hz, 1 H) 9,55 (s, 1 H) 12 25 (br S 1 1 H).
  • Example 5-26 1H NMR (400 MHz, DMSO-d6) ⁇ ppm 1,80 - 2.03 (m, 3 H) 2,27 - 2,31 (m, 1 H) 2.39 - 2.52 (m. 2 H) 2.75 - 2.81 (m, 1 H) 2.85 - 2,89 (m, 1 H) 2.95 - 3.03 (m, 1 H) 3,41 - 3.78 (m, 2 H) 3.90 - 3.99 (m, 1 H) 4.14 - 4.20 (m, 1 H) 4.28 - 4.35 (m, 1 H) 7,28 - 7.37 (m, 3 H) 7.44 - 7,48 (m, 2 H) 7.58 - 7.65 (m ,2 H) 8.45 (br s ,1 H) 12.34 (br s, 1 H),
  • Example 5-32 1H NMR (400 MHz, CD3OD) ⁇ ppm 1.33 - 1.49 (m, 4 H) 1.68 - 1.72 (m, 1 H) 1.79 - 1.83 (m, 1 H) 1.96 - 2.01 (m, 2 H) 2.05 - 2.13 (m, 1 H) 2.17 - 2.25 (m, 1 H) 2.43 - 2.55 (m, 2 H) 2.80 - 2.95 (m, 2 H) 4.42 - 4.49 (m, 1 H) 7.28 - 7.32 (m, 3 H) 7.38 - 7.43 (m, 2 H) 7.52 - 7.59 (m, 4 H).
  • Example 5-33 1H NMR (400 MHz, DMS0-d6) ⁇ ppm 2.48 - 2.55 (m, 2 H) 2.84 - 2.96 (m, 2 H) 4.44 - 4.53 (m. 1 H) 6.94 (br » 1 H) 7.30 - 7.35 (m, 3 H) 7.42 - 7.46 (m, 2 H) 7,57 - 7.64 (m, 4 H) 8.17 - 8.60 (br m, 5 H) 12.27 (br s, 1 H).
  • Example 5-34 1H NMR (400 MHz, CD3OD) ⁇ ppm 1.30 (t, J * 7.0 Hz, 3 H) 2.39 - 2.56 (m, 6 H) 2.82 - 2.93 (m, 2 H) 4.02 (q, J » 7.0 Hz 1 2 H) 4.42 - 4.40 (m, 1 H) 6.96 - 7.03 (m, 2 H) 7.23 • 7.28 (m, 4 H) 7.44 (d, J » 8.4 Hz 1 2 H).
  • Example 5-44; 1H NMR (400 MHz, CD 3 OD) ⁇ ppm 2.64 (d, J-5.8 Hz, 2 H) 3.01 (d. J 6.8 Hz 1 2 H) 4.51 - 4.74 (m, 1 H) 7.00 (br. s., 1 H) 7.25 - 7,35 (m, 3 H) 7.40 (t, J-7.6 Hz, 2 H) 7.53 (d, J-8.1 Hz, 2 H) 7.58 (d, J «8.1 Hz, 2 H) 8.21 (br.
  • Example 5-49 1H NMR (400 MHz, DMSOd 6 ) ⁇ ppm 2.51 - 2.62 (m, 2 H) 2.84 (dd, J- 13.7, 7.9 Hz, 1 H) 2.91 (dd, J*13.7, 7.9 Hz, 1 H) 3.73 (s. 3 H) 4.42 - 4.55 (m. 1 H) 7.05 - 7.19 (m,
  • Example 5-50: 1H NMR (400 MHz 1 CD 3 OD) 6 ppm 2.69 (d, J 6.8 Hz, 2 H) 2.95 - 3.10 (m, 2 H) 4.68 - 4.79 (m, 1 H) 7.21 - 7.33 (m, 1 H) 7.33 - 7.47 (m, 4 H) 7.49 - 7.65 (m, 4 H) 7.76 - 7.97 (m. 2 H) 8.20 - 8,42 (m, 1 H)
  • Example 5-66 1H NMR (400 MHz, CD 3 OD) ⁇ ppm 2.31 - 2.58 (m, 6 H) 2.68 - 2.99 (m, 2 H) 3.63 (S, 3 H) 4.33 - 4.56 (m, 1 H) 6,92 - 7.18 (m, 3 H) 7.30 - 7.38 (m, 1 H) 7.38 - 7.46 (m, 2 H)
  • Example 6-1 Synthesis of (/?)-3-(bJphenyl-4-ylmethyl)-4-(2-carboxyethy!amJno)-4- oxob ⁇ tanoic acid
  • Example 7-2 1H NMR (400 MHz, OMSO-d6) ⁇ ppm 1.51-1.58 (m, 2 H) 2.12 - 2.21 (m, 3 H) 2.49- 2,65 (m, 2 H) 2.81 - 2.89 (m, 2 H) 2.94 - 3.08 (m, 2 H) 7.26 (d, 2 H. J * 8.1 Hz) 7.32 - 7.36 (m, 1 H) 7.43-7.46 (m, 2 H) 7.57 (d. 2 H, J * 8.0 Hz) 7.63-7.65 (m, 2H).
  • Example 8-1 Synthesis of (R)-4-
  • Example 9 > 1 Synthesis of ( ⁇ )-4-biphenyl-4-yl-3- ⁇ (1W « tetrazoJe-S-carbonyl)-a m ⁇ °J- butyric acid
  • Example 11-9 1H NMR (400 MHz, CD 3 CN+D 2 O) ⁇ ppm 2,43 - 2.56 (m, 2 H) 2.71 - 2.91 (m, 4 H) 3.21 - 3.34 (m. 2 H) 4.39 - 4.46 (m, 1 H) 7.27 (d, J ⁇ 8.3 Hz 1 2 H) 7.34 - 7.49 (m, 7 H)
  • Example 11-10 1 H NMR (400 MHz, CD 3 OD) ⁇ ppm 2.38 - 2.41 (m, 2 H) 2.47 - 2.58 (m, 4 H) 2.85 - 2.90 (m, 1 H) 2.99 - 3.04 (m, 1 H) 4.48 ⁇ 4.55 (m, 1 H) 7.32 - 7.44 (m, 5 H) 7.53 -
  • Example 11-17 1H NMR (400 MHz, DMSO-d6) ⁇ ppm 2.46-2.60 (m, 2H), 2.83-2.98 (m, 2H),
  • Example 11-25 1H NMR (400 MHz, DMSO-d6): ⁇ ppm 2.54-2.59 (m, 1H), 2.64-2.70 (m, 1H), 2.88-2.93 (m, 1H), 2.98-3.03 (m, 1H), 4.56-4.65 (m, 1H), 7.13-7.18 (m.
  • Example 11-27 1H NMR (400 MHz, DMSO-d6) 6 ppm 2.51-2.57 (m, 1H) 1 2.64-2.70 (m, 1H), 2.84-2.89 (dd, >6.06 Hz, 1H).
  • Example 11-44 1H NMR (400 MHz 1 DMSO ⁇ d6) ⁇ ppm 2.20-2.39 (m, 4H) 1 2.65-2.87 (m, 2H) 1 4.37-4.56 (m, 1H), 4.91 (d.
  • Example 11-49 1H NMR (400 MHz, DMSO-d6) ⁇ ppm 2.39 - 2.50 (m. 2 H) 2.77 - 2.89 (m, 2 H) 3.61 - 3.71 (m, 2 H) 3.81 (s, 2 H) 4.26 - 4.35 (m. 1 H) 7.31 (d, J ⁇ 8.3 HZ, 2 H) 7.40 - 7,43 (m, 1 H) 7.47 - 7.50 (m, 1 H) 7.62 - 7.65 (m, 3 H) 7.69 - 7.70 (m, 1 H) 8.49 (d, J ⁇ 7.3 Hz 1 1 H).
  • Example 12-1 Synthesis of (/?)-4 ⁇ (1-carboxy-3-(3'*chlorobipheny(-4 ⁇ yl)propan-2- ylamino) ⁇ 4-oxobutanoic acid
  • Example 14-1 Synthesis of (R)-3>(3-Carboxymethyl-ur ⁇ Jdo)-4-(3'"Chlor ⁇ " biphenyl-4-yl
  • Example 16*1 N-[(R)'M3'-chtoro-foiplienyl ⁇ 4 «ylfnethyl)-3-meti)dnesulfonylamino4-oxo» propylj-succinamic acid
  • Example 16-3 1H NMR (400 MHz, DMSO-d ⁇ ) ⁇ ppm 2.24-2,31 (m, 2 H), 2.34-2.40 (m, 2 H),
  • Example 16-5 Synthesis of N-C(R)-I -(3'-chloro-biphenyl-4-ytmethyl)-3- methanesulfonyIamino-3-oxo-propyl]-succinamic acid butyl ester

Abstract

The present invention provides a compound of formula I' or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R5, B1, X and n are defined herein. The invention also relates a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Description

SUBSTITUTED AMINOPROPIONIC DERIVATIVES AS NEPRILYSIN INHIBITORS
BACKGROUND OF THE INVENTION
Endogenous atrial natriuretic peptides (ANP), also called atrial natriuretic factors (ANF) have diuretic, natriuretic and vasorelaxant functions in mammals. The natural ANF peptides is metabofically inactivated, in particular by a degrading enzyme which has been recognized to correspond to the enzyme neutral endopeptidase (NEP) EC 3.4,24.11 , also responsible for e.g. the metabolic inactivation of enkephalins.
Neutral endopeptidase (EC 3.4.24.11; enkephalinase; atriopeptidase; NEP) is a zinc- containing metalloprotease that cleaves a variety of peptide substrates on the amino side of hydrophobic residues [see Pharmacol Rev, Vol. 45, p. 87 (1993)]. Substrates for this enzyme include, but are not limited to, atrial natriuretic peptide (ANP, also known as ANF), brain natriuretic peptide (BNP), met- and leu-enkephalin, bradykinin, neurokinin A, endothelin-1 and substance P. ANP is a potent vasorelaxant and natriuretic agent [see J Hypertens, Vol. 19, p. 1923 (2001)]. Infusion of ANP in normal subjects resulted in a reproducible, marked enhancement of natriuresis and diuresis, including increases in fractional excretion of sodium, urinary flow rate and glomerular filtration rate [see J CHn Pharmacol, Vol. 27, p. 927 (1987)]. However, ANP has a short half-life in circulation, and NEP in kidney cortex membranes has been shown to be the major enzyme responsible for degrading this peptide [see Peptides, Vol. 9, p. 173 (1988)]. Thus, inhibitors of NEP (neutral endopeptidase inhibitors, NEPi) should increase plasma levels of ANP and, hence, are expected to induce natriuretic and diuretic effects.
This enzyme is involved in the breakdown of several bioactive oligopeptides, cleaving peptide bonds on the amino side of hydrophobic amino acid residues. The peptides metabolised include atrial natriuretic peptides (ANP), bombesin, bradykinin, calcitonin gene- related peptide, endothelins, enkephalins, neurotensin, substance P and vasoactive intestinal peptide. Some of these peptides have potent vasodilatory and neurohormone functions, diuretic and natriuretic activity or mediate behaviour effects.
SUMMARY OF THE INVENTION:
The aim of the present invention is to provide novel compounds which are useful as neutral endopeptidase inhibitors, e.g. as inhibitors of the ANF-degrading enzyme in mammals, so as to prolong and potentiate the diuretic, natriuretic and vasodilator properties of ANF in mammals, by inhibiting the degradation thereof to less active metabolites. The compounds of this invention are thus particularly useful for the treatment of conditions and disorders responsive to the inhibition of neutral endopeptidase (NEP) EC 3.4.24.11.
Thus, the compounds of the invention, by inhibiting the neutrai endopeptidase EC.3.4.24.11, can potentiate the biological effects of bioactive peptides. Thus, in particular the compounds have utility in the treatment of a number of disorders, including hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fjbrosis.atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD)1 pulmonary arterial hypertension, renal failure (including edema and salt retension), cyclical oedema, Menteres disease, hyperaldosteroneism (primary and secondary) and hypercalciuria, ascites, in addition, because of their ability to potentiate the effects of ANF the compounds have utility in the treatment of glaucoma. As a further result of their ability to inhibit the neutral endopeptidase E.C.3.4.24.11 the compounds of the invention may have activity in other therapeutic areas including for example the treatment of menstrual disorders, preterm labour, pre-eclampsia , endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovarian syndrome, implantation failure). Also the compounds of the invention should treat asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure sores), septic shock, the modulation of gastric acid secretion, the treatment of hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications and athereosclerosis, male and female sexual dysfunction, In a preferred embodiment the compounds of the invention are useful in the treatment of cardiovascular disorders.
The invention pertains to the compounds, methods for using them, and uses thereof as described herein. Examples of compounds of the invention include the compounds accoring to anyone of Formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof, and the compounds of the examples.
The invention therefore provides a compound of the formula (P):
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is H, C1-7alkyl, hydroxy, C1-7alkoxy, halogen, -SH, -S-CwaikyJ or NRaRb;
R2 for each occurence, is independently d.7alky{, halo, NO2, CN1 C1-7aJkanoylamino, C3.
7cycloalkyl, hydroxy, C1-7alkoxy, haioC1-?alkyl, -NRaRb, Cβ.ioai"yl, heteroaryl or heterocyclyl; wherein Ra and Rb for each occurrence are independently H or C1-7alkyl;
R3 is A1 -C(O)X1 or A?-R4;
R4 is Cβ.toaryl or a heteroaryl, which can be monocyclic or bicyclic, and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, hydroxyC/alkyl, nitro, -NRaRb, -C(O)C1-7alkyi, C(O)-O-Cwalkyl, C1-
7alkoxy, halo, C^alkyl, halo-C1-7akyi, C2-7alkenyl, C6.ioaryl, heteroaryl, -NHSOa-C1- ^alkyl and benzyl; or R4 is a heterocyclyl which can be optionally substituted with one or more substituents independently selected from the group consisting of oxo, hydroxy, hydroxyC1-
7aikyl, amino, C(O)-O- C1-7alkyl, C1-7alkoxy, halo, C1-/alkyl, hafo-C1,7akyl, C6-ioaryl, heteroaryl,
-NHSO2-C1-7aikyl and benzyl;
Rs is H, halo, hydroxy, C1-7alkoxy, halo, C1-?alkyf or halo-C1-7akyl; and
X and X1 are independently OH, -O-C1-7alkyl, -NR9R6, -NHS(O)2-C1-7alkyl, -NHS(O)2-benzyl or -O- Cβ-ioaryl; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C^^aryl, heteroaryl, heterocyclyl,
C(O)NH2, C(O)NH- C1-6alkyl, and C(O)N(C ,.ealkyl)2;
B1 is -C(O)NH- or -NHC(O)-; A1 is a bond or a linear or branched C1-7alkylene ; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C3.τcycioalkyt,
C1 -7alkoxy, hydroxy and O-acetate; in which two gemtnal aikyl can optionally combine to form a C^/cycloalkyl; or
A1 is a linear or branched C1-7alkenylene; or
A1 is a linear 0%A alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NRC; and A1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and C1^alkyl; in which
Rc for each occurrence, is independently H, d.yalkyl, -C(O)-O-C ^alkyl or -CH2C(O)OH; or
A1 is a phenyl or a heteroaryl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of C1-7alkyl, C^cycloalkyi, haio-Cwafkyl, hydroxy, C1^aIkOXy, halo, -NRaRb, -OCH2CO2H1 and -OCH2C(O)NH2; or
A1 is a C^cycloalkyl;
A1 is -C1^alkylene-Cg.io-aryl-, -CMalkylene-heteroaryl- or -Ct^alkylene-heterocyclyi-, wherein
A1 may be in either direction; and
A2 is a bond or a linear or branched C1-? alkylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-7aikoxy, hydroxy, O-Acetate and Cs.rcycloalkyl; n is O, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocycfyi is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S.
The invention therefore provides a compound of the formula (I);
Figure imgf000006_0001
Formula or a pharmaceutically acceptable salt thereof, wherein:
R1 is H or C^alkyl;
R2 for each occurence, is independently C1-7alkyl, halo, NO2, CN. C1-7alkanoylamino, C3.
7cycloalkyl, hydroxy, C1-7aikoxy, halod.raikyl, -NR8R6, C6-ioaryl, heteroaryt or heterocyclyf; wherein Ra and Rb for each occurrence are independently H or C1-7aikyl;
R3 is A1-C(0)X1 or A2~R4;
R4 is C6.ioary! or a heteroaryl, which can be monocyclic or bicycfic, and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, hydroxyd-yalkyi, amino, C(O)-O- d^alkyf, d^aJkoxy, halo, C1-7aikyl, halo-C1-7akyl, C6.i0aryi, heteroaryl, -NHSOK-C1-7alky! and benzyl; or R4 is a heterocyclyi which can be optionally substituted with one or more substituents independently selected from the group consisting of oxo, hydroxy, hydroxyC1-7alkyl, amino, C(O)-O- d.7a!kyl, d.yalkoxy, halo,
Cwafkyl, halo-C1-7akyl, Ce.ioaryl, heteroaryi, -NHSO2-d.7alkyl and benzyl;
Rδ is H, halo, hydroxy, C1-?aikoxy, halo, C1-7aikyl or halo-d-7akyl; and
X and X1 are independently OH, -O-C^alkyl, NRaRb, or -O- C6.ioaryi; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ce-ioaryl, heteroaryl, heterocyclyi, C(O)NH2, C(O)NH- C,.βalkyl, and C(O)N(C1- ea!kyl)2;
B1 is -C(O)NH- or -NHC(O)-;
A1 is a bond or a linear or branched Ct.7aikylene ; which is optionally substituted with one or more substituents independently selected from the group consisting of haio, C3.7cycioalkyl,
C^alkoxy, hydroxy and O-acetate; in which two gemtnal alkyl can optionally combine to form a C^cycloaikyi; or
A1 is a phenyl or a heteroaryl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of Chalky!, C^-cycloalkyl, halo-C1-7aikyl, hydroxy, C1-7afkoxy, halo, ~NRaRb, -OCH2COxH, and -OCH2C(O)NH2; or
A1 is a C3.7cycloalkyl;
A1 is -C1^alkylene-Cβ.10-aryl-, -d^alkylene-heteroaryi- or -C1^alkylene-heterocyclyl-, wherein
A1 may be in either direction; and
A2 is a bond or a linear or branched C1-? alkylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-7alkoxy, hydroxy, O-Acetate and Cs.7cycioafkyl; n is 0, 1, 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicycltc aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S,
In another embodiment, the invention pertains to a method for treating a disorders or diseases responsive to the inhibition of neutral endopeptidase EC 3.4. 24.11 (NEP)1 in a subject, by administering to the subject a therapeutically effective amount of a compound according to anyone of Formulae V and I to VIIC. or a pharmaceutically acceptable salt thereof, such that the disorder or disease responsive to the inhibition of neutral endopeptidase EC 3.4. 24.11 (NEP) in the subject is treated.
In yet another embodiment, the invention pertains to a method for treating hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathey, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis.atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD)1 pulmonary arterial hypertension, renal failure (including edema and salt retension), cyclical oedema, Menieres disease, hyperaldosteroneism (primary and secondary) and hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders (especially mate and female infertility, polycystic ovarian syndrome, implantation failure), asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure sores), septic shock, gastric acid secretion dysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metaboiic syndrome, diabetic complications and atherosclerosis, male and female sexual dysfunction; comprising administering to the subject a therapeutically effective amount of a compound according to anyone of of Formulae I' and I to VIIC, or a pharmaceutically acceptable sait thereof, such that the subject is treated.
In yet another embodiment, the invention pertains to pharmaceutical compositions, comprising of a compound according to anyone of Formulae I1 and I to VIIC, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
In still another embodiment, the invention pertains to combinations including a compound according to anyone of Formulae V and I-VIC, or a pharmaceutically acceptable salt thereof, and pharmaceutical combinations of one or more therapeutically active agents.
In another embodiment, the invention pertains to a method for inhibiting neutral endopeptidase EC 3,4. 24.11 in a subject by administering to the subject a therapeutically effective amount of a compound according to anyone of Formulae i' and I to VIIC, or a pharmaceutically acceptable salt thereof, such that neutral endopeptidase EC 3.4, 24,11 is inhibited.
DETAILED DESCRIPTION OF THE INVENTION:
Compounds of the Invention
References hereinafter to compounds of Formula I or V apply equally to compounds according to anyone of Formulae IA to VIiC.
References hereinafter to embodiments of the invention apply equally to compounds of Formula I or C and compounds according to anyone of Formulae IA to VIIC, insofar as the embodiments are present.
Various embodiments of the invention are described herein, ft will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments.
In one embodiment the invention provides a compound of the Formula I or !', or a pharmaceutically acceptable salt thereof, wherein: R1 is H or C1^aIkVl;
R2 for each occurence, is independently C1^alkyl, halo, Ca.7cycloalkyl, hydroxy, C1-7aikoxy, haloC1-7alkyl, ~NRaRb, C6.ioaryl, heteroaryl or heterocyclyl; wherein Ra and Rb for each occurence are independently H or C1^alkyl; R3 is A1-C(O)X1 or A2~R4; R4 is Ce-ioaryl or a heteroaryl, which can be monocyclic or bicycftc and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, C1-7alkoxy, halo, d.^alkyi, halo-C1-7akyl C6-ioaryl, heteroaryl, -NHSO2- d.7alkyl and benzyl;
R5 is H; and
X and X1 are independently OH, -O-C1-7a!kyl or NRsRb;
B1 is -C(O)NH- or -NHC(O)-;
A1 is a linear or branched C1-7alkylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C^cycloalkyi, C1-
/aikoxy, hydroxy and O-acetate, in which two geminal alkyl can optionally combine to form a
C3.7cycloalkyl; or
A1 is a phenyl or a heteroaryl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of Chalky!, C3.7cycloaJkyl, halo-C1-7aikyl, hydroxy, C1-7alkoxy, halo, -NR*Rb, -OCH2CO2H, and -OCH2C(O)NH2; and
A2 is a bond or a linear or branched C1-/ alkyfene: which is optionally substituted with one or more substituents independently selected from the group consisting of hafo, C1-7alkoxy, hydroxy^ O-Acetate and C^cycloalkyl; and n is 0, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms. wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S.
Certain compounds of Formula I or I' include compounds of Formula IA wherein the stereochemistry at the carbon bearing the biphenyl group is (R):
Figure imgf000010_0001
Formula IA. or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, B1- R3 and n have the definitions of Formula I or I', supra.
In one embodiment, the invention pertains to compounds of Formula I or I' or a pharmaceutically acceptable salt thereof, wherein n is 1 , 2, 3, 4 or 5; R2 is halo and is attached to the meta position and the other optional Rz groups are independently C1-7alkyl. NO2, CN1 halo, C3-7cycloalkyl, hydroxy, C1^aIkOXy, halo-Cv7alkyl, NRbRc, C6 ioaryl, heteroaryl or heterocyclyl. This embodiment is illustrated by compounds of Formulae IB and IC:
Figure imgf000011_0001
Formula IB Formula IC or a pharmaceutically acceptable salt thereof, wherein X1 R1, R2, B1, R3 have the definitions of Formula I or I1, supra: p is 0, 1, 2, 3 or 4 and R2a is halo.
Certain compounds of Formula I or C include compounds of Formula II.
Figure imgf000011_0002
Formula il or a pharmaceutically acceptable salt thereof, wherein X1 X1, A\ R1, R2 and n have the definitions of Formula I or I', supra,
In a further embodiment, the invention pertains to compounds of Formula M wherein the stereochemistry of the carbon bearing the biphenyi groups is (R). This embodiment is illustrated by compounds of Formula HA:
Figure imgf000012_0001
Formula HA or a pharmaceutically acceptable salt thereof, wherein X, X1, A1, R1, R2 and n have the definitions of Formula I or Ϋ, supra.
Certain compounds of Formula I, I1 or Il include compounds of Formula MB or HC:
Figure imgf000012_0002
Figure imgf000012_0003
Formula HB Formula HC or a pharmaceutically acceptable salt thereof, wherein X, X\ A1, R1, R2 have the definitions of Formula I or I', supra; p is 0, 1 , 2, 3 or 4 and R2a is halo.
Certains compounds of Formula I or I' include compounds of Formula III:
Figure imgf000012_0004
Formula III or a pharmaceutically acceptable salt thereof, wherein X1 X1, A1, R1, RJ and n have the definitions of Formula I or I', supra
In a further embodiment, the invention pertains to compounds of Formula III wherein the stereochemistry of the carbon bearing the biphenyl groups is (R). This embodiment is illustrated by compounds of Formula IHA
Figure imgf000013_0001
Formula IMA or a pharmaceutically acceptable salt thereof, wherein X, X1. A\ R1, R2 and n have the definitions of Formula I or I1, supra
Certain compounds of Formula Mf include compounds of Formula 1MB or IMC:
Figure imgf000013_0002
Figure imgf000013_0003
Formula IHB Formula IMC or a pharmaceutically acceptable salt thereof, wherein X, X1, A1, R1, R7 have the definitions of Formula I or I1, supra, p is 0, 1, 2, 3 or 4 and R Za is halo.
In another embodiment the invention provides a compound according to anyone of formulae I', I to IC, Ii to HC and IM to MIC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A1 is a linear C^alkylene, which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1^aIkOXy, hydroxy, O-acetate and C3.7cycloaikyl; in which two geminal alkyl can optionally combine to form a C3-7cycloalkyl.
A further embodiment include compounds according to anyone of Formulae I', I to IC, Ii to HC and tli to IHC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt thereof, wherein A1 is -CH2-, -CH2CH2-, -CH2CH2CH2- or A1 has the following formulae:
Figure imgf000014_0001
or
Figure imgf000014_0004
in which Rc1, R02. Rd1, R02, Re\ Re2, Re3 and Re4 are independently H, halo, C^cycloalkyl, or C1-7alkyl; and alternatively Rc1 and R02 or Rd1 and Rd2 can form together with the atoms to which they are attached a Cs^cycloalkyl. In one aspect of this embodiment, A1 is one of the following:
Figure imgf000014_0002
Yet another further embodiment includes compounds according to anyone of Formulae I', I to IC, Il to HC and III to IHC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt thereof, wherein A1 has the following formulae:
Figure imgf000014_0003
in which R'\ Rβ, Rβ and Rf4 are independently H, halo, O-acetate or C1-ralkyl. In a further embodiment, A1 is one of the following: or
Figure imgf000015_0002
Figure imgf000015_0001
In yet another embodiment, the invention provides a compound according to anyone of of Formulae !', I to IC. Il to HC and III to IHC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A1 is a C3. 7cyck>alkyl. Examples of this embodiment are compounds of anyone of Formulae I'. I to IC, Il to MC and III to IKC, wherein A1 is selected from the following:
Figure imgf000015_0003
In yet another embodiment, the invention provides a compound according to anyone of of Formulae I', I to IC1 Il to HC and III to HIC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A1 is a linear or branched C2.raikenylene. An example of C2.7aikenylene is trans CH=CH.
In yet another embodiment, the invention provides a compound according to anyone of of Formulae I'. I to IC, Il to IIC and III to HIC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A1 is a linear C1.4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NRC; and A1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and C^alkyl; in which Rc for each occurrence is indepenctenently H, C^alkyl, -C(O)O d.yalkyl or CH2C(O)OH. One further embodiment includes compounds of Formulae I', I to IC1 Il to IfC and ill to NIC wherein A1 is one of the following:
Figure imgf000016_0001
In yet another embodiment, the invention provides a compound according to anyone of of Formulae I', I to IC. Il to HC and IM to IHC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A1 is optionally substituted phenyl or heteroaryl, wherein optional substituents are defined as in Formula 1 or
Certain compounds of the above embodiment include compounds according to anyone of Formula I', I to IC1 H to HC and IH to IHC or a pharmaceutically acceptable salt thereof, wherein A1 is a 5-membered ring heteroaryl. This embodiment is illustrated by compounds of Formula IV:
Figure imgf000016_0002
Formuia IV or a pharmaceutically acceptable salt thereof, wherein X, X1, B1, R1, R2 and n have the definitions of Formula I or I", supra and and Y1, Y2 and Y3 are independently N1 NH, S, O or CH and form together with the ring atoms to which they are attached a 5-membered heteroaryl ring.
In one aspect of this embodiment, the invention pertains to compounds of Formula IVA:
Figure imgf000017_0001
Formula IVA or a pharmaceutically acceptable salt thereof, wherein X, X\ B1, R1, R2, Y1, Y7, Y3 and n have the definitions of Formulae I, I' or IV. supra.
In one aspect of this embodiment, Y1, Yz and Y3 form together with the ring atoms to which they are attached a 5-membered heteroaryl ring selected from furan, thiophene, pyrrofe, pyrazole, oxazote, thiazole, oxadiazole, thiadiazoie, and triazole. One further embodiment includes compounds of Formula IV or ViA, or a pharmaceutically acceptable salt thereof, wherein the 5-membered heteroary! is one of the following:
Figure imgf000017_0002
Figure imgf000018_0001
In a further embodiment, the invention pertains to compounds of Formula IV or IVA wherein n is 1 , 2, 3, 4 or 5; Rz is halo in the meta position and the other optional R2 groups are independently Chalky!, NO*, CN, halo, C^cyctoalkyl, hydroxy, C1^aIkOXy, halo-d^alkyl, NRbRc, C6.iOaryl, heteroaryl or heterocyclyl.
In yet another aspect of the above embpdiment, the invention pertains to compounds of Formula P, I to IC, Il to HC or III to IHC1 or a pharmaceutically acceptable salt thereof, wherein A1 is a 5-membered ring heteroaryl attached to the amide B1 at a nitrogen atom. This embodiment is illustrated by compounds of Formulae V or VA:
Figure imgf000018_0002
Figure imgf000018_0003
Formula V Formula VA or a pharmaceutically acceptable salt thereof, wherein X, X1, B1, R1, R2 and n have the definitions of Formula I or I', supra and each Y4 are independently N, S1 O or CH. In a further embodiment, the invention pertains to compounds of Formula V or VA wherein n is 1 , 2, 3, 4 or 5; R2 is halo in the meta position and the other optional R2 groups are independently C^aikyi, NO?, CN, haio, Ca^cycloafkyl, hydroxy, C1-7alkoxy, hafo-Cvralkyl, NRbRc, Cβ-toaryl, heteroaryl or heterocyclyl.
!n yet another aspect of the above embodiment the invention provides a compound according to anyone of Formulae P, I to IC, Il to HC and III to HIC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A1 is a phenyl or a 6-membered ring heteroaryl in which phenyl and heteroaryl are optionally substituted with d^aikyl, C3.7cycloalkyl, halo-C1-7alkyl, hydroxy, C^alkoxy, halo, NRaRb, -OCHjfCOjH, or -OCHxC(O)NHj. One aspect of this embodiment include compounds according to anyone of Formulae I1, 1 to IC, If to HC and IM to HIC, or pharmaceutically acceptable salt thereof, wherein A1 is connected to the amide B1 and to the C(O)X1 moieties in a para arrangement. Another aspect of this embodiment include compounds according to anyone of Formula I', I to IC, Il to IfC and HI to HIC wherein A1 is connected to the amide B1 and to the C(O)X1 moieties in a meta arrangement. Compounds of this embodiment include compounds of Formula Vl.
Figure imgf000019_0001
Formula Vl or a pharmaceutically acceptable salt thereof, wherein X, X1, B1, R1, R2 and n have the definitions of Formula I or I', supra and W1, W2, W3 and W4 are independently N or CRe, in which each Rθ is independently H, C^alkyi, C3.?cycloalkyl, halo-Chalky!, hydroxy, C1- raikoxy, halo, -NRaRb, -OCH2CO2H or -OCH2C(O)NH2 In one aspect of this embodiment A1 is phenyl, pyridine or pyrimidine.
In a further embodiment, the invention pertains to compounds of Formula VIA:
Figure imgf000019_0002
Formula VIA or a pharmaceutically acceptable salt thereof, wherein X, X1, B1, R1, R2, W1, W?, W3 and W4 and n have the definitions of Formulae I1 1* or Vl, supra.
One further embodiment includes compounds of Formula Vl or VIA, or a pharmaceutically acceptable salt thereof, wherein A1 is one of the following:
Figure imgf000020_0001
OH ,
In a further embodiment, the invention pertains to compounds of Formula Vl or VIA, or a pharmaceutically acceptable salt thereof, wherein n is 1 , 2, 3, 4 or 5; R2 is halo in the meta position and the other optional R2 groups are independently C1^aIKyI, NO2, CN, halo, C3- rcycloalkyl, hydroxy, C1-7alkoxy, halo-C^alkyl, NRbRc, CVioaryl, heteroaryl or heterocyclyl.
In one aspect of the previous embodiment, the invention pertains to compounds according to anyone of Formulae I', I to IC, IV to IVC, V to VC and Vl to VIC, or pharmaceutically acceptable salt thereof, wherein B1 is -C(O)NH-. In another embodiment, B1 is -NHC(O)-.
Certain compounds of the above embodiment include compounds according to anyone of Formulae I1, 1 to IC, Il to MC and III to IHC. or a pharmaceutically acceptable salt thereof, wherein A1 is -d^alkylene-Ce-io-aryl-, -CMalkylene-heteroaryl- or -C1^alkylene- heterocyclyh -Ce-ioaryl-C^-alkylene-, -heteroaryl-CMalkylene or -heterocyclyl-C^alkylene-. In one aspect of this embodiment, A1 is -C1Λaikylene-CfMo-aryl-, -Ct^alkylene-heteroaryl- or - CMalkylene-heterocyclyk wherein the alkylene portion is attached to B1 amide group and the aryl, heteroaryl or heterocyclyl moittes are attached to C(O)X1. In another aspect of this embodiment, A1 is -CH2-phenyl- or -phenyl-CH;?-. In another aspect of this embodiment, A1 is -CH2-heteroaryi or -heteroaryl-CHa-. In a further embodiment, A1 is -CHz-heterocyclyl or -heterocyclyl-CHj-. Representative examples of A1 are the following:
Figure imgf000021_0001
Certain compouncte of Formula I or C include compounds of Formula VIi:
R1
Figure imgf000021_0002
Formula VII or a pharmaceutically acceptable satt thereof, wherein X, A2, R1, R2, R4 and n have the definitions of Formula I or I', supra. A further embodiment includes compounds of Formula V(IA:
Figure imgf000021_0003
Formula VIIA or a pharmaceutically acceptable sait thereof, wherein X, A2, R1, R2, R4 and n have the definitions of Formula I or V, supra.
Certain compounds of Formula VII or VIIA have the formula VIIB or V)IC:
Figure imgf000022_0001
Formula VIIB Formula Vl IC or a pharmaceutically acceptable salt thereof, wherein X1 A2, R1, R2, R4 have the definitions of Formula I or I', supra; p is 0, 1, 2, 3 or 4 and R2a is halo.
A further aspect of this embodiment include compounds according to anyone of Formulae VII to VIIC1 or a pharmaceutically acceptable salt therof, wherein A2 is (CH2)P and p is 0, 1 , 2, 3. In one aspect of this embodiment p is O1 therefore A2 is a bond. In another aspect of this embodiment A2 is CH≥ or CH2-CH2.
In another aspect of this embodiment the invention provide compounds according to anyone of Formulae VII to VIIC1 or a pharmaceutically acceptable salt thereof, wherein R4 is optionally substituted C$.iOaryl. Representative examples of aryl are benzoimidazolone, benzoisothiazolone or phenyl. In one further aspect of this embodiment, R4 is phenyl. Substituents on the phenyl ring include for example, halo {e.g. F, Ci), hydroxy, halo-C)-7alkyl (e.g. CF3), -NHS(O)2-C1-7alkyl, heteroaryl, C1-7aikoxy or d.7alkyl.
In yet another aspect of this embodiment the invention provides compounds according to anyone of Formula VII to VIIC or a pharmaceutically acceptable salt thereof, wherein R4 is an optionally substituted bicyclic heteroaryl.
In yet another aspect of this embodiment the invention provide compounds according to anyone of Formulae VII to VIIC or a pharmaceutically acceptable salt thereof wherein R4 is optionally substituted 5- or 6-membered heteroaryl. In one aspect of this embodiment, RΛ is a 6-membered ring heteroaryl selected from the group consisting of pyrazinyl, pyridinyl, pyrimidinyl, oxo-pyranyl (e.g. pyranone, optionally substituted pyran-4-one, pyran-2-one such as 3-hydroxy-pyran-4-one. 3-hydroxy-pyran-2-one), and oxo-pyridtnyl (e.g. pyridinone, optionally substituted pyπdin-4-one or pyridin-2-one such as for example 3-hydroxy-1-methyl- pyridin-4-one or 1~benzyl-pyridin-2-one), or pyrimidinone (i.e oxo-pyrimidinyl). In another aspect of this embodiment R4 is a 5-membered ring heteroaryi selected from the group consisting of oxazole, pyrrole, pyrazole, isooxazoie, triazoie, tetrazole, oxacliazole (e.g. 1- oxa-3,4-diazote. 1-oxa-2,4-diazole), oxadiazolone {e.g. oxadiazol-2-one), thiazole, isothiazofe, thiophene, imidazole and thiadiazole. Other representative examples of R* are oxazolone, thiazolone, oxadiazolone, triazolone, oxazoJone, imidazolone, pyrazolone. In a further embodiment, the optional sυbstituents on Cβ-ioβryl and heteroaryl are selected from hydroxy, C1-7alkyl, C1-7aikoxy, halo, ha!o-C1-τaikyt or benzyl.
In yet another aspect of the above embodiment the invention provide compounds according to anyone of Formulae VII to VIIC or a pharmaceutically acceptable salt thereof, wherein R4 is a bicyclic heteroaryl. A further embodiment includes compounds according to anyone of Formulae VII to VIIC, or a pharmaceutically acceptable salt thereof, wherein R" is indole, benzothiazole or benzimidazole. Representative examples of R4 are the following:
Figure imgf000023_0001
Figure imgf000024_0001
In yet another aspect of the above embodiment the invention provide compounds according to anyone of Formulae VII to VIIC, or a pharmaceutically acceptable salt thereof wheretn R4 is a monocyclic saturated or partjaily saturated heterocyclyi, which heterocyclyl contains at least one heteroatom selected from nitrogen, sulfur and oxygen, and which heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of oxo, hydroxy, C1-7alkoxy, halo, Chalky!, halo-C1-7akyi, C6.iøaryl, heteroaryl, -NHSO2-C1-7afkyl and benzyl. In one particular aspect of this embodiment, R4 is pyrrolidine or imidazoline, wherein the heterocyclyl may be linked to the carbonyl (C(O)-A2) moiety via a carbon or a nitrogen and the heterocyclyl ts optionally substituted with oxo.
In one embodiment the invention provide compounds according to anyone of Formulae l\ I to IC, Il to MC, III to IHC IV, IVA1 V, VA, Vl, VIA and VII to VIIC or a pharmaceutically acceptable salt thereof, wherein R1 is H
In another embodiment the invention provide compounds according to anyone of Formulae I', I to IC, Il to HC1 III to IMC, IV1 IVA1 V, VA, Vl, VIA and VII to VIIC, or a pharmaceutically acceptable salt thereof, wherein each R2 is independently halo, Chalky!, C1^aIkOXy1 hydroxy, halo-C1 7alkyl and n is O, 1 or 2 In a further embodiment n is 1, 2, 3, 4 or 5, R2 is halo in the meta position and the other optional R2 groups are independently halo, C1-7alkyl, C^ralkoxy, hydroxy or haloalkyl. In yet a further embodiment, the invention provide compounds according to anyone of Formulae P1 I to IC, Il to HC, Ml to IHC, IV, IVA, V1 VA, Vl, VIA and VII to VIIC, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2, R2 is meta-chloro or meta-fiuoro and the other optional R2 group is halo, C1-7alkyt, C^aikoxy, hydroxy or haloalkyl.
In yet another embodiment the invention provide compounds according to anyone of Formulae P1 1 to IC, Il to HC, IN to MfC, I1 IVA, V, VA, Vl1 VIA and VII to VIIC, or a pharmaceutically acceptable salt thereof, wherein X and X1 are independently OH or -O-C1- 7alkyl (e.g. -O-ethyl, -O-methyl or ~O-nbutyl). In one particular aspect of this embodiment X and X1 are OH. In another aspect of this embodiment, X and X1 are independently -O-C1- 7alkyl in which alkyl is substituted with Cβ-ioaryl, heteroaryi, heterocyclyl, C(O)NH2, C(O)NH- C^alkyt, or C(O)N(C^alkyl)2. Representative examples of X or X1 are -O-CH2-C(O)N(CH3)2, -O-CHa-CHa-morpholine, -O-CH2-dioxo}one or -O-benzyl. In yet another aspect of this embodiment, X and X1 are -O-C6.i<>aryl. A representative examples of -0-C6.ioaryl is -O-(2,3- dihydro-1H-indene).
In another embodiment X, X1, B1, A1, A2, R2, R1 and RA groups are those defined by the X, X1, A1. A2, B1. R2, R1 and R4 groups in the Examples section beiow.
In another embodiment individual compounds according to the invention are those listed in the Examples section below, or a pharmaceutically acceptable salt thereof.
Definition
For purposes of interpreting this specification, the following definitions will apply unless specified otherwise and whenever appropriate, terms used in the singular will also include the plural and vice versa.
As used herein, the term '-alkyl" refers to a fully saturated branched or unbranched (or straight chain or linear) hydrocarbon moiety, comprising 1 to 20 carbon atoms. Preferably the alkyl comprises 1 to 7 carbon atoms, and more preferably 1 to 4 carbon atoms. Representative examples of alkyl include methyl, ethyl, n-propyl, /so-propyl, n-butyl, sec-butyl, /so-butyl, tert-butyl, π-pentyl, isopentyl, neopentyl, n-hexyf, 3-methyJhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl. The term "C1-7alkyl" refers to a hydrocarbon having one to seven carbon atoms. Moreover, the term alkenyl includes both "unsubstituted alkyls " and "substituted alkyls". The term "alkylene" refers to a divalent alkyl radical, wherein alkyl is as previously defined. The term "alkenyT refers to a branched or unbranched hydrocarbon having at teast one carbon-carbon double bond. The term "C2-7aikenyr refers to a hydrocarbon having two to seven carbon atoms and comprising at least one carbon-carbon double bond. Representative examples of alkenyi are vinyl, prop-1-enyl, alfyl, butenyl, isopropenyl or isobutenyl. The term "alkeylene" refers to a divalent alkenyi radical, wherein alkenyi is as previously defined.
As used herein, the term "haloalkyl" refers to an alkyl as defined herein.that is substituted by one or more halo groups as defined herein. Preferably the haloalkyl can be monohaloaikyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloro or fiuoro within the alkyl group. Dihaloalky and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Preferably, the polyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups. Representative examples of haioalkyl are fluoromethyl. difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyi. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms. The term "halo-Chalky!" refers to a hydrocarbon having one to seven carbon atoms and being substituted by one or more halo groups.
As used herein, the term "alkσxy" refers to alkyl-O-, wherein alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, te/t-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. Preferably, alkoxy groups have about 1-7, more preferably about 1-4 carbons.
As used herein, the term "cycloalkyl" refers to saturated or unsaturated but non- aromatic monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, preferably 3-8, or 3-7 carbon atoms. For bicydic, and tricyclic cycloaikyt system, all rings are non-aromatic. Exemplary monocyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyciopentyl, cyclopentenyl, cycfohexyl and cyclohexenyf. Exemplary bfcyclic hydrocarbon groups include bσrnyl, decahydronaphthyl, bicyclo(2.1.1Jhexyl, bicyclo{2.2.1]heptyl, bicyclof2.2.1]heptenyl, bicyclo[2.2.2]octyl. Exemplary tricyclic hydrocarbon groups include adamantyl. The term "C3.7cycloakyr refers to a cyclic hydrocarbon groups having 3 to 7 carbon atoms. The term "cycloaikylalkyl" refers to an alkyl susbtituted with cycloalkyl,
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-10 carbon atoms in the ring portion. The term "aryl" also refer to a group in which the aromatic ring is fused to a cycloalkyl ring, where the radical of attachment is on the aromatic ring or on the fused cycloalkyt ring Representative examples of aryi are phenyl, naphthyl, hexahydroindyl, indanyl or tetrahydronaphthyl The term "C6 loaryl" refers to an aromatic hydrocarbon groups having 6 to 10 carbon atoms in the ring portion
The term "arylalkyl" is an aikyl substituted with aryl. Representative examples of arylalkyl are benzyl or Phenyl-CH2CH?- The term also includes substituted arylalkyl moiety
The term ' Heteroaryr includes monocyclic or bicyclic heteroaryl. containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms and each heteroatoms is indepdendently selected from O, N or S wherein S and N may be oxidized to vaπous oxidation states. For bicyclic heteroaryl system, the system is fully aromatic (ι e. al! rings are aromatic).
Typical monocyclic heteroaryl groups include thienyl, furyl, pyrrolyl, imtdazojyl, pyrazolyl, thiazolyl, isothiazotyl, oxa-2,3-diazolyl, oxa-2,4-diazolyl, oxa-2.5-dιazolyl, oxa-3,4- diazolyl, thιa-2,3-diazofyl, thιa-2,4-diazolyl, thιa-2,5-diazolyl, thιa-3,4-dιazolyl, 3-, A-, or 5- tsothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazoiyl, 3- or 5-1 ,2,4-trιazolyl, 4- or 5-1 ,2, 3- triazolyl, tetrazolyl, 2~, 3-, or 4-pyrιdyl, 3- or 4-pyrιdazιnyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazιnyl, 2- , 4-, or 5-pyπmιdιnyl
The term "heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyi rings, where the radical or potnt of attachment is on the heteroaromatic ring or on the fused aryl rmg. Representative examples of bicydic heteroaryl are indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, quinolizinyl, quinoliny}, isoquinoKnyl, cinnolinyl, phthalaztny!, naphthyridinyl, quinazolmyl, quinaxalinyl, thιeno{2,3-b]furanyl, furo{3,2-b]-pyranyl, δH-pyrido^^-dJ-o-oxazinyl, 1H-pyrazoJo[4,3-d]- oxazolyl, 4H-tmιdazo{4>5-d] thiazolyl, pyrazιno[2,3-d]pyπdazinyl, imιdazo{2 1-b] thiazoiyl, imιdazo[1,2-b][1 ,2,4]trιazιnyl, 7~benzo[b]thienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzoxapinyl, benzoxazinyl, 1H-pyrrolo[1,2-b]{2Jbenzazapinyf, benzofuryl, benzothiophenyl benzotnazolyl, pyrrolo{2,3-b]pyπdιnyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-c]pyridιnyl, pyrrolo(3,2-b3pyridinyl, ιmidazo[4 5-bJpyridιnyi, imidazoH.δ-cJpyπdinyl, pyrazoio{4,3- d]pyridιnyl, pyrazolo[4 3-c)pyridιny!( pyrazolo[3,4-cjpyndtnyl, pyrazolo[3,4-djpyrιdιnyl, pyrazoio[3,4-b]pyrιdιnyl, ιmιdazo|1 ,2-a)pyrιdιnyl, pyrazolo{1 ,5-a]pyridιnyl, pyrrolo{1 2- bjpyπdazinyl, imtdazo{1,2~c3pyrimιdιnyl, pyndo[3,2-d]pyrimtdinyl, pyrιdo[4,3-d}pyrιmιdtnyf, pyrido[3,4-d}pyrimιdinyl, pyridot2,3-d]pyrimidinyl, pyrιdo[2,3-b]pyrazinyl, pyrido{3,4- bjpyrazmyl, pyrιmido[5,4-d)pyrιmιdιnyi, pyrazιno[2,3-b]pyrazιnyl, or pyrιmιdo[4,5-djpy«mιdinyi When a heteroaryf moiety is substituted with hydroxy, the invention also pertains to its oxo tautomeric. For example, an oxadiazoie substituted with hydroxy also includes oxo- oxadiazole or also known as oxadiazolone. The tautomerisation is represented as follow:
Figure imgf000028_0001
As used herein, the term "heterocyclyl" or "heterocydo" refers to an optionally substituted, saturated or unsaturated non-aromatic (partially unsaturated) ring which is a 4-, 5-, 6-, or 7-membered monocyclic, and contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states. For bicyclic and tricyclic heterocyclyl ring system, a non-aromatic ring system is defined as being a non-fully or partially unsaturated ring system. Therefore bicyclic and tricyclic heterocyclyl ring systems includes heterocyclyl ring systems wherein one of the fused rings is aromatic but the other(s) is (are) non-aromatic. In one embodiment, heterocyclyl moiety represents a saturated monocyclic ring containing from 5-7 ring atoms and optionally containing a further heteroatom, selected from O, S or N. The heterocyclic group can be attached at a heteroatom or a carbon atom. The heterocyclyl can include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include dihydrofuranyf, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithioiane, oxathianyl, thiomorpholino, oxirany), aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, piperazinyl, azepinyl, oxapinyl, oxaazepanyl, oxathianyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl.
The term "hydroxyalkyl" refers to alkyl groups, as decrtbed above, in which the afkyl group is substituted with one or more hydroxy.
The term "halogen" includes fluorine, bromine, chlorine and iodine. The term "perhalogenated" generally refers to a moiety wherein ail hydrogens are replaced by halogen atoms.
The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. In another embodiment, the heteroatom is nitrogen, oxygen or sulfur-
It will be noted that the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemical^ controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application afso include ail tautomers thereof.
As used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms. Also as used herein, the term "an optical isomer" or "a stereoisomer" refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non- superimposabie mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a "racemtc" mixture. The term is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S, Resolved compounds whose absolute configuration is unknown can be designated (+) of (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycioalkyl, the cycloalkyl substituent may have a cis- or transconfiguration. All tautomeric forms are also intended to be included.
Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R1S)- configuration. In certain embodiments, each asymmetric atom has at least 50 % enantiomerlc excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.
Accordingly, as used herein a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optica! isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyf tartaric acid, di-O,O'-p-to1uoyi tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chJral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
As used herein, the term "pharmaceutically acceptable salts1' refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edtsylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsuiphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate. pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, sυccinate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycoiic acid, pyruvic acid, oxalic acid, maleic acid, rnalonic acid, succinic acid, fυmaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesuifonic acid, ethanesulfonic acid, p~ toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases, inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived inciude, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropyiamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanoiamine. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na1 Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences', 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahi and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. For example, any hydrogen represented by "H" in any of the formulae herein is intended to represent all tsotoptc forms of hydrogen (e.g. 1H, 2H or D, 3H); any carbon represented by "C" in any of the formulae herein is intended to represent all isotopic forms of carbon (e.g. 11C, 13C, 14C); any nitrogen represented by "N" is intended to represent all isotopic forms of nitrogen (e.g. 14N, 16N). Other examples of isotopes that are included in the invention include isotopes of oxygen, sulfur, phosphorous, fluorine, iodine and chlorine, such as 18F 31P, 32P, 35S1 38CI, 125I, The invention includes vartous isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3H, 13C, and 14C are present. In one embodiment, the atoms in the formulae herein occur in their natural abundance. In another embodiment, one or more hydrogen atom may be enriched in 2H; or/and one or more carbon atom may be enriched in 11C1 13C or 14C; or/and one or more nitrogen may be enriched in 14N. Such isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopicafly labeled reagent.
Further, enrichment with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound according to anyone of the formulae I' and I to VIIC. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term Isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at ieast 4000 (60% deuterium incorporation), at ieast 4500 (67.5% deuterium incorporation), at ieast 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at ieast 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
Isotopically-enriched compounds of formulae I' or I to VIIC can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-enriched reagent in place of the non-enriched reagent previously employed Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, dβ-acetone, dδ-DMSO.
Compounds of the invention, i.e. compounds accroding to anyone of formulae I' and I to VIIC, that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co- crystals may be prepared from compounds according to anyone of formulae !' and I to VIIC by known co-crystal forming procedures. Such procedures include grinding, heating, co- subliming, co-melting, or contacting in solution compounds according to anyone of formulae I' and I to VIiC with the co-crystal former under crystallization conditions and isolating co- crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound according to anyone of formulae I' and I to VIIC.
As used herein, the term "pharmaceutically acceptable carrier" includes any and ail solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example. Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount' refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by neutral endopeptidase EC 3.4. 24.11 or (ii) associated with neutral endopeptidase EC 3.4. 24.11 activity, or (iii) characterized by abnormal activity of neutral endopeptidase EC 3.4. 24.11 ; or (2) reducing or inhibiting the activity of neutral endopeptidase EC 3.4. 24.11; or (3) reducing or inhibiting the expression of neutral endopeptidase EC 3.4. 24.11. In another non-limiting embodiment the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non- ceiiular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of neutral endopeptidase EC 3.4. 24.11; or at least partially reducing or inhibiting the expression of neutral endopeptidase EC 3.4. 24.11.
As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. A subject also refers to for example, primates {e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In a preferred embodiment, the subject is a human.
As used herein, the term "inhibition" or "inhibiting0 refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
As used herein, the term "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context,
The term "hypertension" refers to a condition where the pressure of blood within the blood vessels is higher than normal as it circulates through the body, When the systolic pressure exceeds 150 mmHg or the diastolic pressure exceeds 90 mmHg for a sustained period of time, damage is done to the body. For example, excessive systolic pressure can rupture blood vessels anywhere, and when it occurs within the brain, a stroke results. Hypertension may also cause thickening and narrowing of the blood vessels which ultimately could lead to atherosclerosis. The term "type 2 diabetes" including type 2 diabetes associated with hypertension refers to a disease in which the pancreas does not secrete sufficient insulin due to an impairment of pancreatic beta-cell function and/or in which there is to insensitivity to produced insulin (insulin resistance). Typically, the fasting plasma glucose is less than 126 mg/dL, while pre-diabetes is, e.g., a condition which is characterized by one of following conditions: impaired fasting glucose {110-125 mg/dL) and impaired glucose tolerance (fasting glucose levels less than 126 mg/dL and post-prandial glucose level between 140 mg/dL and 199 mg/dL). Type 2 diabetes meliitus can be associated with or without hypertension. Diabetes meliitus occurs frequently, e.g., in African American, Latino/Hispanic American, Native American, Native American, Asian American and Pacific Islanders. Markers of insulin resistance include HbAIC, HOMA IR, measuring collagen fragments, TGF-β in urine, PAI-1 and prorenin.
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and ail examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
Compounds of the present invention are either obtained in the free form, as a salt thereof, or as prodrug derivattves thereof.
When both a basic group and an acid group are present in the same molecule, the compounds of the present invention may also form interna) salts, e.g., zwitterionic molecules.
The present invention also provides pro-drugs of the compounds of the present invention that converts in vivo to the compounds of the present invention. A pro-drug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject. The suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art. Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego. Calif., 2001). Generally, bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity. Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve υptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety Is acceptably non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize a moiety that provides slow release, e.g., certain polymers or other moieties, such as cyciodextrins. Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased iipophHicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property). For example, IipophHicity can be increased by esteriftcation of (a) hydroxy! groups with lipophilic carboxyltc acids (e.g., a carboxylic acid having at least one lipophilic moiety), or (b) carboxylic add groups with lipophilic alcohols (e.g., an alcohol having at least one lipophilic moiety, for example aliphatic alcohols).
Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has a meaning as defined herein. Preferred are pharmaceutically acceptable ester derivatives convertible by soivojysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or dt-substiiuted lower aikyl esters, such as the ω-(amino, mono- or di-iower alkylamino, carboxy, lower alkoxycarbonyl)- lower alkyl esters, the α-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-fower alkyl esters, such as the pivaloyloxymethy! ester and the like conventionally used in the art. In addition, amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)). Moreover, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. GENERAL SYNTHETIC ASPECTS
The compounds of the invention can be synthesized using the methods described in the following schemes, examples, and by using art recognized techniques. All compounds described herein are included in the invention as compounds. Compounds of the invention may be synthesized according to at least one of the methods described in schemes 1 -4.
Within the scope of this text, only a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated a "protecting group", unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W, McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999.
Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se. For example, salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used. Acid addition salts of compounds of the present invention are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent. Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.
Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
Mixtures of isomers obtainable according to the invention can be separated in a manner known per se into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by e.g. medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisorners so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.
Intermediates and final products can be worked up and/or purified according to standard methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like.
The following applies in general to all processes mentioned herein before and hereinafter.
All the above-mentioned process steps can be carried out under reaction conditions that are known per se, including those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, including, for example, solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g. in the H+ form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from about -100 °C to about 190 °C, including, for example, from approximately -80 °C to approximately 150 °C, for example at from -80 to «60 °C1 at room temperature, at from -20 to 40 °C or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere.
At all stages of the reactions, mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described under "Additional process steps".
The solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethytformamtde or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or tø-methylpyrrolidin-2- one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methycyclohexane, or mixtures of those solvents, for example aqueous solutions, unless otherwise indicated in the description of the processes. Such solvent mixtures may also be used in working up, for example by chromatography or partitioning.
The compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
The invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).
The compounds of the invention according to anyone of formulae I1 and ) to VIIC can be prepared by the procedure described in the following sections. Abbreviations:
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0004
The compounds of the invention of formula Il can be prepared by hydrolysis of intermediates A to C wherein X1 X1, A1, R1, R2 and n have the definition of Formula I or I', supra; and P1 and P2 are appropriate protecting groups selected from, but not limited to, methyl, ethyl, isopropyl, tert-butyl, methoxybenzyl or benzyl.
Figure imgf000041_0001
Figure imgf000041_0002
Intermediate A Intermediate B
Figure imgf000041_0003
Intermediate C The compounds of the invention of formula IM can be prepared by hydrolysis of intermediate D, E or F wherein X, X1, A1, R1, R2 and n have the definition of Formula I or I', supra, and P1 and P2 can be appropriate protecting groups selected from, but not limited to, methyl, ethyl, isopropyl, tert-butyl. methoxybenzyi or benzyl.
Figure imgf000042_0001
Figure imgf000042_0002
intermediate D intermediate E
Figure imgf000042_0003
Intermediate F
The compounds of the invention of formula VII can be prepared by hydrolysis of intermediate G wherein A2, R1, R2, R4 and n have the definition of Formula I or )', supra, and P1 can be appropriate protecting group selected from, but not limited to, methyl, ethyl, isopropyl, tert- butyl, methoxybenzyi or benzyl.
Figure imgf000042_0004
Intermediate G
Standard methods can be applied for the hydrolysis of lntermeidates A to G using a base selected from, but not limited to, NaOH, KOH or LiOH. or an acid selected from, but not ltmited to, TFA or HCt. When P1 or P3 is benzyl or methoxybenzyl, preferable method of deprotection is hydrogenation in the presence of a catalyst such as, but not limited to, palladium-on-carbon under hydrogen.
The intermediate A, B, C or G can be prepared using the following process comprising; condensing an intermediate H or I wherein X1 P\ R1, R2 and n are as previously described:
Figure imgf000043_0001
Figure imgf000043_0002
Intermediate H Intermediate I with an intermediate J, K or L wherein X1, A1, A2, R4 and P5 are previously described.
Figure imgf000043_0003
Figure imgf000043_0004
Figure imgf000043_0005
Known condensation methods may be applied including, but not limited to, conversion of the intermediate J, K or L to their corresponding acid halide, using reagents such as thiony) chloride or oxalyl chloride, or conversion of intermediate J, K or L to mixed anhydride using reagents such as CIC(O)O-isobutyl or 2 ,4,6-irichlorobenzoyi chloride followed by reaction of the acid halide or mixed anhydride with the intermediate H or I in a presence or absence of a base such as tertiary amine (e.g. triethylamine, DIPEA1 or N«methylmorpholine) or pyridine derivative (e.g. pyridine, 4-(dimethylamino)pyridine, or 4-pyrrolidinopyridine). Alternatively, the intermediate J, K, or L can be coupled with H or I using coupling reagents such as DCC, EDCI, PyBOP or BOP in presence or absence of a reagent such as 1- hydroxybenazotriazole, 1-hydroxy-7-azabenzotriazole or peπtafluorophenoi.
Intermediate G wherein R4 is a tetrazole can be synthesized according to Scheme 1 : R1 V '
P1
Figure imgf000044_0001
Scheme 1 wherein A2, R1, R2, R*. P1, P2 and n are as previously defined above.
In step 1a, intermediate I is reacted with an appropriate carboxylic acid using standard coupling reagents selected from, but not limited to, DCC, EDCI, PyBOP or BOP in presence or absence of a reagent such as 1-hydroxybenazotriazole, 1-hydroxy-7-azabenzotriazole or pentafluorophenol; follwoed by removal of P2 protecting group in step 1c using a base selected from, but not limited to, NaOH, KOH or LiOH, or an acid selected from, but not limited to, TFA or HCI, or hydrogenation with a catalyst such as, but not limited to, palladium- on-carbon under hydrogen. Alternatively, intermediate I is reacted with an appropriate anhydride in the presence of a base selected from, but not limited to, pyridine, triethylamine or diisopropylethylamine (step 1b); followed by conversion of the carboxylic acid into a tetrazole (step 1b) using similar method as described in Journal of Medicinal Chemistry 1998, 41 , 1513.
The intermediate D, E or F can be prepared using the following process comprising: condensing an intermediate M wherein X1 P1, R1, R2 and n are as defined above;
Figure imgf000045_0001
Figure imgf000045_0002
Jntermediate M Intermediate N with an intermediate Q or S wherein X1, A1 and P2 have the meaning as defined above.
Figure imgf000045_0003
Figure imgf000045_0004
Known condensation methods may be applied including, but not limited to, conversion of the intermediate M or N to acid halide, using reagents such as thionyl chloride or oxalyl chloride, or conversion of intermediate M or N to mixed anhydride using reagents such as CIC(O)O-isobutyl or 2,4.6-trichlorobenzoyl chloride followed by reaction of the acid chloride or mixed anhydride with the intermediate Q or S in a presence or absence of a base such as tertiary amine (e.g. triethylamine, DIPEA, or N-methylmorphoitne) or pyridine derivative (e.g. pyridine. 4-(dimethylamino)pyridine, or 4-pyrrolidinopyridine); Alternatively, the intermediate M or N can be coupled with the intermediate Q or S using a reagent such as DCC, EDCl, PyBOP or BOP in presence or absence of a reagent such as 1~hydroxybenazotriazole, 1- hydroxy-7-azabenzotriazole or pentafluorophenol.
The intermediate M or N can be prepared according to the following genera! procedures described in Scheme 2:
Figure imgf000046_0001
wherein R\ Ra, X and n are as defined above and wherein m = O or 1 ; P1 is a protecting group selected from, but not limited to, hydrogen, methyl, ethyl, propyl, tørf-butyl, methoxymethyl, tert-butyldimethylsilyi, tetrahydrofuranyl, benzyl, ally) or phenyl; R5 is for example hydrogen, methyl, ethyl, isopropyl, benzyl or phenyl; R6 and R7 are independently hydrogen, methyl, ethyl, isopropyl, benzyl or phenyl. Y is selected from, but not limited to, chloro, bromo, iodo, benzotriazoloxy, pyridinium, N,Λklimethylaminopyridinium, pentafluorophenoxy, phenoxy, 4-chlorophenoxy, -OCO2Me, -OCO^Et, tert-butoxycarbonyi or ~OCC(O)O-isobutyl.
In step (2a), standard methods can be applied to prepare the corresponding acid halide, such as the use of thionyl chloride, oxalyl chloride; or standard methods to prepare the mixed anhydride or the acyl pyridinium cation can be applied, such as the use of pivaloyl chloride with a tertiary amine (e.g. triethylamtne, DIPEA, N-methylmorphoϋne) in the presence or absence of a pyridine derivative (e.g. pyridine, 4-(dimethylamino)pyridtne, 4- pyrroJidinopyridine), 2,4,6-trichlorobenzoyl chloride with a tertiary amine (e,g, triethylamine, DIPEA, W-methylmorphoHne) in the presence or absence of a pyridine derivative (e.g. pyridine, 4-(dimethylamino)pyridine, 4-pyrrolidinopyridine), or CiC(O)O-Z-Bu with a tertiary amine (e.g. triethylamine, DIPEA. N-methylmorpholine) tn the presence or absence of a pyridine derivative (e.g. pyridine, 4-(dimethylamino)pyridine, 4-pyrrolidinopyrtdine); or standard methods to prepare the activated ester can be applied, such as the use of 1- hydroxybenazotriazole, 1-hydroxy-7-azabenzotriazole or pentafluorophenol in the presence of a coupling reagent (e.g. DCC1 EDCI) or BOP.
In step (2b), standard methods to prepare the N-acyk>xazolidinones (m = O) can be employed, illustrative examples of this chemistry are outlined in Afdrichchimica Acta 1997, Vol. 30, pp. 3 - 12 and the references therein; or standard methods to prepare the N- acyloxazinanone (m ~ 1) can be employed. An illustrative example of this chemistry is outlined in Organic and Bt'omolecular Chemistry 2006, Vol. 4, No. 14, pp. 2753 - 2768. In step (2c), Standard methods for alkylation can be employed. An illustrative example is outlined in Chemical Reviews 1996, 96(2), 835 - 876 and the references therein. In step (2d), standard methods for cleavage of N-acyloxazoHdinone or N-acyloxaztnanone can be employed. Illustrative examples of this chemistry are outlined in Aldrichchimica Acta 1997, Vo. 30, pp. 3 - 12 and the references therein.
The intermediate H or I can be prepared according to the following general procedures described in Schemes 3 and 4:
Figure imgf000047_0001
wherein R1, R2, X and n are as defined above and wherein P3 is a protecting group selected from, but not limited to, te/t-butyt, benzyl, tπphenylphosphynyl, tert-bυtoxycarbonyl, benzyloxycarbonyl, ailyloxycarbonyl, acetyl or trifluoroacetyl.
In step (3a), standard methods for introduction of the amine part can be employed, such as using: either simultaneous treatment with or stepwise treatment via the corresponding acyl azide formation by using thionyl chloride (or CICO2R8), NaN3 (or TIvISN3) and R8OH {wherein R6 and R9 are hydrogen, methyl, ethyl, tert-butyl, allyl, benzyl or 4-methoxybenzyl); or either simultaneous treatment with or stepwise treatment via the corresponding acyl azide formation with DPPA and R9OH (wherein R9 is defined as above); or standard methods for conversion to the corresponding carboxamide followed by treatment with NH3 equivalent and either simultaneous treatment with or stepwise treatment with LTA or hypervalent iodine reagents (e.g. PIDA, PIFA1 PhI(OH)OTs1 PhIO) and R9OH (wherein R9 is defined as above); or standard methods for conversion to the corresponding carboxamide and either simultaneous treatment with or stepwise treatment with Br2 and MOH {wherein M is defined herein e.g. Na, K, Ba or Ca); or standard methods for conversion to the corresponding carboxamide and treatment with MOZ or NaBrO2 (wherein Z is defined herein e.g. Cl or Br); or standard methods for conversion to the corresponding carboxamide and treatment with Pb(OAc)4 and R9OH (wherein R9 is defined as above); or standard methods for conversion to the corresponding hydroxamic acid followed by treatment with H2NOH or H2NOTMS and treatment with Ac2O, BoC2O, R10COCI1 R10SO2CI, R10PO2CI (wherein R10 is defined herein e.g. Me, Et, tBu or phenyl), thtonyl chloride, EDCl, DCC1 or 1-chloro-2.4-dinitrobenzene in the presence or absence of a base (e.g. pyridine, Na2C03aq, triethytømine, DIPEA) and treatment with R9OH in the presence of a base (e.g. DBU, ZOH1 DIPEA) (wherein R9 and Z are defined as above).
In step (3b), standard methods for removing P3 protecting groups can be applied, such as base hydrolysis using NaOH1 KOH, or LiOH, acid hydrolysis using TFA or HCl, or hydrogenation using palladium-on-carbon under hydrogen.
Scheme 4 describes an alternative synthesis of Intermediate H or I;
Figure imgf000048_0001
wherein LG is a leaving group selected from, but not limited to, Cl, Br1 1, OMs, OTs or OTf. In step (4a), standard methods for Arndt-Eistert homologation can be employed. An illustrative example of this chemistry is outlined in Εnantioselective synthesis of β-amino acids, Tύ Edition", John Wiley and Sons, Inc., NJ (2005), either directly or analogously.
In step (4b), standard methods for afkylation can be employed, such as using R1LG in the presence of a base such as LDA, NHMOS, LHMDS or KHMDS
In step (4c), standard methods to protect the carboxylic aαd can be employed, such as using TMSCHN2 (for methyl ester), P'LG/base (e.g K2CO3, NaHCO3, Cs2CO3 or K3PO4), thionyl chloride (or oxalyl chlorιde)/RsOH, DCC(Or EDCI)/DMAP/R9OH, BOP/R9OK (or
R9ONa)1 (R9O)2CHNMe2, CDI/DBU/ R9OH wherein Rθ has the same meaning as defined above, or isobutylene/H2S04 (for tert-butyl ester)
In step (Ad), standard methods for Suzuki coupling reaction can be applied, such as using a palladium (or nickel) species [e g Pd(PPh3).), PdCI?(dppf), Pd(OAc)s/a phosphine (e g PPh3, dppf, PCy3, P(tBu)3, XPhos), PaIC1 Pd2(dba)j/ a phosphine (e g PPh3, dppf, PCy3, P(tBu)3>
XPhos), Ni(COD)2Za phosphine (or dppe, dppb, PCy3), Ni(dppf)CI2). a base (e g KF, CsF,
K3PO4, Na2CO3, K2CO3, Cs2CO3, NaOH1 KOH, NaO-f-Bu, KO-Z-Bu), and (R2)n-PhB(OH)2 [or
(RVPhBF3K].
In step (4e), standard methods for removing P3 protecting groups can be applied, such as base hydrolysis using NaOH, KOH, or LiOH, acid hydrolysis using TFA or HCI, or hydrogenation using palladium-on-carbon under hydrogen
Alternatively, the intermediate H or I may be prepared be following the synthetic routes outlined in Tetrahedron Letters, 2008, VoI 49, No. 33, pp 4977-4980 either directly or analogously and converting the obtained boronic actd into a substituted biphenyl by methods outlined in Organic Letters, 2002, Vol. 4, No. 22, pp 3803 - 3805
Alternatively, the intermediate H or I may be prepared be following the synthetic routes outlined in Tetrahedron. Asymmetry, 2006, VoI 17, No. 2, pp 205-209 either directly or analogously
Alternatively, the intermediate H or I may be prepared by methods of Mannich reaction Illustrative examples of this chemistry are outlined in "Enantioselective synthesis of β-amino aαds, 2na Edition", John Wiley and Sons, inc., NJ (2005), either directly or analogously
Alternatively, the intermediate H or I may be prepared by enolate addition Illustrative examples of this chemistry are outlined in "Enantioselective synthesis of β-amino acids, 2nd Edition", John Wiley and Sons, Inc., NJ (2005), either directly or analogously Aiternatively, the intermediate H or I may be prepared by methods of aza-Michael reaction. Illustrative examples of this chemistry are outlined in Εnantiosetective synthesis of β-amino acids, 2πct Edition", John Wiley and Sons, Inc., NJ (2005), either directly or analogously.
Alternatively, the intermediate H or I may be prepared following the synthetic route outlined in Synlett, 2006, No. 4, pp, 539-542, either directly or analogously.
The synthesis of intermediates J, K and L is also described in US patent application of applicant docket number PAT053600-US-USP3 which was filed on Aprii 16, 2010, which application is incorporated herein by reference.
The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.
Compounds of the invention and intermediates can also be converted into each other according to methods generally known per $e.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition can be formulated for particufar routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form including capsules, tablets, pills, granules, powders or suppositories, or in a liquid form including solutions, suspensions or emulsions. The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as welt as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers etc.
Typically, the pharmaceutical compositions are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or poiyethylenegrycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, algintc acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
Tablets may be either film coated or enteric coated according to methods known in the art.
Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersibte powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure andtor buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
Suitable compositions for transdermal application include an effective amount of a compound of the invention with carrier. Carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayabte formulations, e.g., for delivery by aerosol or the like, Such topical delivery systems will in particular be appropriate for dermal application. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art. Such may contain sotubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
As used herein a topical application may also pertain to an inhalation or to an intranasal application. They are conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.
Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g. , vials), blister packs, and strip packs.
The invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
The compounds according to anyone of formulae I' and I to VIIC in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. neutral endopeptidase EC 3.4. 24.11 modulating properties, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
Compounds of the invention, or a pharmaceutically acceptable salt thereof, may be useful in the treatment of an indication selected from: cardiovascular disorders, such hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, cyclical oedema, Menieres disease, hyperaldosteroneism (primary and secondary) and hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-edampsia, endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovarian syndrome, implantation failure), asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure sores), septic shock, the modulation of gastric acid secretion, the treatment of hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, diabetic complications and atherosclerosis, male and female sexual dysfunction.
Thus, as a further embodiment, the present invention provides the use of a compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof. In a further embodiment, the therapy is selected from a disease which is ameliorated by inhibition of neutral endopeptidase EC 3.4. 24.11. In another embodiment, the disease is selected from the afore-mentioned list, suitably hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure (including edema and salt retension), diabetic nephropathy, non- diabetic nephropathy, type-2 diabetis, and diabetic complications and most suitably cardiovascular disorders, such as hypertension, renal insufficiency including edema and congestive heart failure. )n another embodiment, the invention provides a method of treating a disease which is ameliorated by the inhibition of neutral endopeptidase EC 3.4. 24.11 comprising administration of a therapeutically acceptable amount of a compound according to anyone of formulae I', J1 IA, II, HA, III, IHA, IV, IVA, V, VA, Vl, VIA and VII to VIIC, or a pharmaceutically acceptable salt thereof. In a further embodiment, the disease is selected from the aforementioned list, suitably hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure (including edema and salt retension); diabetic nephropathy, non-diabetic nephropathy, type-2 diabetes, and diabetic complications and most suitably cardiovascular disorders, such as hypertension, renal insufficiency including edema and congestive heart failure.
The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredϊent(s) for a subject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenteral^, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 103 molar and 10*δ molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 rng/kg, or between about 1-100 mg/kg.
The activity of a compound according to the present invention can be assessed by the following in vitro & in vivo methods and/or by the following in vitro & in vivo methods well- described in the art. See A fluorescence lifetime-based assay for protease inhibitor profiling on human kallikrein 7 Doering K, Meder G, Hinnenberger M, Woelcke J, Mayr LM, Hassiepen U Biomol Screen. 2009 Jan; 14(1):1-9. In particular, the in vitro inhibition of recombinant human neutral endopeptidase (NEP, EC 3.4.24,11) can be determined as follows:
Recombinant human neutral endopeptidase (expressed in insect cells and purified using standard methods, final concentration 7 pM) is pre-incubated with test compounds at various concentrations for 1 hour at room temperature in 10 mM sodium phosphate buffer at pH 7.4, containing 150 mM NaCI and 0.05 % (w/v) CHAPS. The enzymatic reaction is started by the addition of a synthetic peptide substrate Cys(PT14)-Arg-Arg-Leu-Trp-OH to a final concentration of 0.7 μM. Substrate hydrolysis leads to an increase fluorescence lifetime (FLT) of PT14 measured by the means of a FLT reader as described by Doering et al. (2009). The effect of the compound on the enzymatic activity was determined after 1 hour (t ~ 60 min) incubation at room temperature. The IC50 values, corresponding to the inhibitor concentration showing 50% reduction of the FLT values measured in absence of inhibitor, are calculated from the plot of percentage of inhibition vs. inhibitor concentration using nonlinear regression analysis software.
Using the test assay (as described above) compounds of the invention exhibited inhibitory efficacy in accordance to Table 1 , provided infra.
Table 1 1nhibitory Activity of Compounds
Figure imgf000055_0001
The compound of the present invention may be administered either simultaneously with, or before or after, at least one other therapeutic agent. The compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition.
In one embodiment, the invention provides a product comprising a compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition associated with neutral endopepttdase EC 3.4. 24.11 activity. Products provided as a combined preparation include a composition comprising the compound of formulae I' and I to VIIC and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof, and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
In one embodiment, the invention provides a pharmaceutical composition comprising a compound according to anyone of formulae I' and I to VIIC1 or a pharmaceutically acceptable salt thereof, and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound according to anyone of formulae I1 and I to VIIC1 or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.
In the combination therapies of the invention, the compound of the invention, or a pharmaceutically acceptable salt thereof and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention, or a pharmaceutically acceptable salt thereof, and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
Accordingly, the invention provides the use of a compound according to anyone of formulae !' and I to VIIC1 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11. activity, wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent in the manufacture of medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11. activity, wherein the medicament is prepared for administration with a compound according to anyone of formulae f and I to VIIC1 or a pharmaceutically acceptable salt thereof.
The invention also provides a compound according to anyone of formulae I1 and I to VtIC, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11 activity, wherein the compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof, is prepared for administration with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11 activity, wherein the other therapeutic agent is prepared for administration with a compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof. The invention also provides a compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11 activity, wherein the compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof, is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11 activity, wherein the other therapeutic agent is administered with a compound according to anyone of formulae I' and I to VIIC, or a pharmaceutically acceptable salt thereof.
The invention also provides the use of a compound according to anyone of formulae !' and I to VIIC, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11 activity, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent in the manufacture of a medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.11 activity, wherein the patient has previously (e.g. within 24 hours) been treated with a compound according to anyone of formulae I' and I to VlIC, or a pharmaceutically acceptable salt thereof.
In one embodiment, the other therapeutic agent is selected from: HMG-Co-A reductase inhibitor, an angiotensin receptor blocker (ARBs, angiotensin M receptor antagonist), angiotensin converting enzyme (ACE) Inhibitor, a calcium channel blocker (CCB)1 an endothelin antagonist, a renin inhibitor, a diuretic, an ApoA-l mimic, an antidiabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, an aldosterone synthase inhibitors (ASI), a CETP inhibitor or a phophodiesterase type 5 (PDE5) inhibitor.
The term "in combination with" a second agent or treatment includes co-administration of the compound of the invention (e.g., a compound of Formulae I' or l-VltC or a compound otherwise described herein) with the second agent or treatment, administration of the compound of the invention first, followed by the second agent or treatment and administration of the second agent or treatment first, foliowed by the compound of the invention.
The term "second agent" includes any agent which is known in the art to treat, prevent, or reduce the symptoms of a disease or disorder described herein, e.g .a disorder or disease responsive to the inhibition of neutral endopeptidase, such as for example, hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD). endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis.atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD), pulmonary arterial hypertension, renal failure (including edema and salt retension), cyclical oedema, Menieres disease, hyperaldosteroneism (primary and secondary) and hypercalciuria. ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia. endometriosis, and reproductive disorders (especially mate and female infertility, polycystic ovarian syndrome, implantation failure), asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition such as dementia and geriatric confusion, obesity and gastrointestinal disorders {especially diarrhea and irritable bowel syndrome), wound healing (especiatly diabetic and venous ulcers and pressure sores), septic shock, gastric acid secretion dysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications and atherosclerosis, male and female sexual dysfunction.
Examples of second agents include HMG-Co-A reductase inhibitors, angiotensin Il receptor antagonists, angiotensin converting enzyme (ACE) Inhibitors, calcium channel blockers (CCB), endothelin antagonists, renin inhibitors, diuretics, ApoA-l mimics, antidiabetic agents, obesity-reducing agents, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase inhibitors (ASI) and CETP inhibitors.
The term "HMG-Co-A reductase inhibitor" (also called beta-hydroxy-beta- methylglutaryl-co-enzyme-A reductase inhibitors) includes active agents that may be used to lower the lipid levels including cholesterol in blood. Examples include atorvastatin, cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin, ffuvastatin, lovastatin, pravastatin, mevastatin, pravastatin, rivastatin, simvastatin, and velostatin, or, pharmaceutically acceptable salts thereof.
The term "ACE-inhibitor" (also called angiotensin converting enzyme inhibitors) includes molecules that interrupt the enzymatic degradation of angiotensin I to angiotensin II. Such compounds may be used for the regulation of blood pressure and for the treatment of congestive heart failure. Examples include alacepril, benazepril, benazeprilat, captopril. ceronapril, cilazapril, delapril, enalapril, enaprifat, fosinoprii, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril. and trandolapπl, or, pharmaceutically acceptables salt thereof.
The term "endothelin antagonist" includes bosentan (cf . EP 526708 A), tezosentan (cf. WO 96/19459), or, pharmaceutically acceptable salts thereof.
The term "renin inhibitor" includes ditekiren (chemical name: [1 S- {1 R*, 2FTAFT(I fl*,2R*)])-H(1.1 -dimethylethoxy)carbonyl)-L-proly l-L-phenyfalanyl-N-[2- hydroxy-5~methyl-1 -(2-methylpropyl)-4-[[[2-methyl-1 -[[(2- pyridinylmrthyl)aminoJcarbonyl]butyl]amino]carbonyl}hexyl3-N-aJfa-methyl-L-histidinamide); terlakiren (chemical name: [R-(f?*lS*)]-N-(4-morpholinylcarbonyl)-L-phenylalany!-N-[1- (cyclohexylmethyO^-hydroxy-S^I-methylethoxy^S-oxopropytJ-S-methyl-L-cystβineamide); Aliskiren (chemical name: (2S,4S,5S7S)-5-amino-N-{2-carbamoyl-2,2-dimethylethyl)-4- hydroxy-7~{[4-methoxy-3-(3-methoxypropoxy) phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide) and zankiren {chemical name: (1 S- [1R*[R*(R*)})2S*.3R*]]-N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-m ethy!hexyl]-aifa-[f2'[((4- methyl-1-piperazinyl)sulfonyl3methyl]-1-oxo-3-phenylpropyt3-amino3-4-thiazo!epropanamide), or, hydrochloride salts thereof, or, SPP630, SPP635 and SPP800 as developed by Speedel, or RO 66-1132 and RO 66-1168 of Formula (A) and (B):
and Of|
Figure imgf000060_0001
Figure imgf000060_0002
pharmaceutically acceptable salts thereof.
The term "aliskiren", if not defined specifically, is to be understood both as the free base and as a salt thereof, especially a pharmaceutically acceptable salt thereof, most preferably a hemi-fumarate salt thereof.
An angiotensin Il receptor antagonist or a pharmaceutically acceptable salt thereof is understood to be an active ingredient which bind to the AT1 -receptor subtype of angiotensin Il receptor but do not result in activation of the receptor. As a consequence of the inhibition of the ATi receptor, these antagonists can, for example, be employed as antihypertensives or for treating congestive heart failure.
The class of ATi receptor antagonists comprises compounds having differing structural features, essentially preferred are the non-peptidic ones. For example, mention may be made of the compounds which are selected from the group consisting of vaisartan, iosartan, candesartan, eprosartan, irbesartan, saprisartan, tasosartan, telmisartan, the compound with the designation E-1477 of the following formula
Figure imgf000061_0001
COOH the compound with the designation SC-52458 of the following formula
Figure imgf000061_0002
and the compound with the designation ZO-8731 of the following formula
Figure imgf000061_0003
or, in each case, a pharmaceutically acceptable salt thereof.
Preferred AT,-receptor antagonist are those agents which have been marketed, most preferred is valsartan or a pharmaceutically acceptable salt thereof.
The term "calcium channel blocker (CCB)" includes dihydropyridines (DHPs) and non-DHPs (e.g., diftiazem-type and verapamil-type CCBs). Examples include amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, nigυldipine, niludipine, ntmodipme, nisoldipine. nitrendipine, and nivaldipine, and is preferably a non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil, or, pharmaceutically acceptable salts thereof. CCBs may be used as anti-hypertensive, anti-angina pectoris, or anti-arrhythmic drugs. The term "diuretic" includes thiazide derivatives (e.g.. chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorothalidon).
The term "ApoA-l mimic" includes D4F peptides (e.g., formula D-W-F-K-A-F-Y-D-K- V-A-E-K-F-K-E-A-F)
The term "anti-diabetic agent" includes insulin secretion enhancers that promote the secretion of insutin from pancreatic β-cells. Examples include biguanide derivatives (e.g., metformin), sulfonylureas (SU) (e.g., tolbutamide, chlorpropamide, tolazamide, acetohexamide, 4-chloro-N-{(1-pyrolidinylamino)carbonyl]-benzensulfonamide (glycopyramtde), glibenclamide (glyburide), gliclazide, 1-butyl-3-metanilylurea, carbutamide, glibonuride, glipizide, gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, and totylcyclamide), or pharmaceutically acceptable salts thereof. Further examples include phenylalanine derivatives (e.g., nateglinide [N- (fr-ans^-isopropylcyclαhβxylcarbonyO-D-phenylaianine] (cf. EP 196222 and EP 526171) of the formula
Figure imgf000062_0001
repaglinide [{S)-2-ethoxy-4-{2~[[3-methyl- 1 ~[2-( 1 -piperidinyl)phenylJbutyl]amino}-2- oxoethyl}benzoic acid] (cf. EP 589874, EP 147850 A2, in particular Example 11 on page 61, and EP 207331 A1); calcium (2S)-2-benzyl-3-(c/s-hexahydro-2-isoindolinlycarbonyl)- propionate dihydrate (e.g., mitiglinide (cf. EP 507534)); and glimepiride (cf. EP 31058). Further examples include DPP-IV inhibitors, GLP-1 and GLP-1 agonists.
DPP-IV is responsible for inactivating GLP-1. More particularly, DPP-IV generates a GLP-1 receptor antagonist and thereby shortens the physiological response to GLP-1, GLP- 1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal.
The DPP-IV inhibitor can be peptidic or, preferably, non-peptidic. DPP-IV inhibitors are in each case generically and specifically disclosed e.g. in WO 98/19998, DE 196 16 486 A1, WO 00/34241 and WO 95/15309, in each case in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications. Preferred are those compounds that are spectfically disclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241, respectively.
GLP-1 is an insulinotropic protein which is described, e.g., by W.E. Schmidt et al. in Diabetologia, 28, 1985, 704-707 and in US 5,705,483.
The term "GLP-1 agonists" includes variants and analogs of GLP-1 (7-36)NH2 which are disclosed in particular in US 5,120,712, US 5,118666, US 5,512,549, WO 91/11457 and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826. Further examples include GLP-1(7- 37), in which compound the carboxy-terminal amide functionality of Arg3δ is displaced with Gly at the 37th position of the GLP-1 (7-36)NH2 molecule and variants and analogs thereof including GLN9-GLP- 1(7-37), D-GLN*-GLP- 1(7-37), acetyl LYS9-GLP« 1(7-37), LYS1β-GLP- 1(7-37) and, in particular, GLP-1 (7-37)OH, VAL8-GLP~1 (7-37), GLY8-GLP-1(7-37), THR8- GLP-1(7-37), MET^-GLP-I (7-37) and 4-imidazopropionyl~GLP~1. Special preference is also given to the GLP agonist analog exendin-4, described by Greig e( a/, in Diabetologia 1999, 42, 45-50.
Also included in the definition "anti-diabetic agent" are insulin sensitivity enhancers which restore impaired insulin receptor function to reduce insulin resistance and consequently enhance the insulin sensitivity. Examples include hypoglycemic thiazolidinedioπe derivatives (e.g., glitazone, (SM(3,4-dihydrσ-2-(phenyl-methy[)-2H-1- benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5-{f4-(3-(5~methyl-2-phenyl-4- oxazolyl)-1 -oxopropy!)-phenylj~methyl}-thiazolidine-2,4-dk>ne (darglitazone), 5-{[4-{1 -methyl- cyclohexyl)methoxy)-pheny{]methyl}-thiazolidine-2,4-d<one (ciglUazone), 5-{[4-<2-(1- indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (DRF2189), 5-{4-f.2-{5-methyl-2-phenyl- 4-oxazolyl)-ethoxy)Jbenzyl}-thiazolidine-2,4-dione (BM-13.1246), 5-(2-naphthy)sυlfonyi)- thiazolidine-2.4-dione (AY-31637), bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268), 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy3benzyl}-thiazoNdine-2,4- dione (AD-5075), 5-[4-(1 -phenyl- 1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2, 4- dione (DN-108) 5-{{4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]methyl}-thtazolidine-2,4-dione, 5-[3-(4-chloro-phenyl))-2-propynyl)-5-phenylsulfonyl)th)azolidine-2,4-dione, 5-[3-(4- chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-214-dione1 5-{[4-(2-(methyl- 2-pyridinyl-amino)-ethoxy)phenyl}methy1Hh<azolidine-2,4-dione (rosiglitazone), 5-{[4-(2-(5- ethy!-2-pyridyl)ethoxy)phenyl]-methy(}thiazoltdine-2l4-dione (pioglitazone), 5-{[4-((3,4- dihydro-6-hydroxy-2.5,7,8-tetramethyl-2H-1-benzopyran-2-yi)methoxy)-phenyl]-methyl}- thiazoltdine-2,4-dione (troglitazone), 5-[6-(2-fluoro-benzyloxy)naphthalen-2-yimethyl]- thiazolidine-2,4-dione (MCC555), 5-{|;2-(2-naphthyl)-benzoxazol-5~yl]-methyl}thtazolidine-2,4- dione (T-174) and 5-(2,4-dioxothiazolidin-5-ylme%l)-2-methoxy-N-{4-trifluoromethyl- benzyl)benzamide (KRP297)).
Further anti-diabetic agents include, insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), antidiabetic non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT); compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (GδPase), inhibitors of fructose-1,6-btsphosphatase (F-1,6-8pase), inhibitors of glycogen phosphorylase (GP)1 glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxylase (PEPCK); pyruvate dehydrogenase kinase (PDHK) inhibitors; inhibitors of gastric emptylng; insulin; inhibitors of GSK-3; retinoid X receptor (RXR) agonists; agonists of Beta-3 AR; agonists of uncoupling proteins (UCPs); non- glitazone type PPARγ agonists; dual PPARoJ PPARy agonists; antidiabetic vanadium containing compounds; incretin hormones, like glucagon-like peptide-1 (GLP-1) and GLP-1 agonists; beta-cell imidazoline receptor antagonists; mtglitol; α2-adrenergic antagonists; and pharmaceutically acceptable salts thereof.
The term "obesity-reducing agent" includes lipase inhibitors (e.g. , oriistat) and appetite suppressants (e.g., sibutramine and phentermine).
An aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof is understood to be an active ingredient that has the property to inhibit the production of aldosterone. Aldosterone synthase (CYP11B2) is a mitochondrial cytochrome P450 enzyme catalyzing the last step of aldosterone production in the adrenal cortex, i.e., the conversion of 11 -deoxycorticosterone to aldosterone. The inhibition of the aldosterone production with so-called aldosterone synthase inhibitors is known to be a successful variant to treatment of hypokalemia, hypertension, congestive heart failure, atrial fibrillation or renal failure. Such aldosterone synthase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., US 2007/0049616).
The class of aldosterone synthase inhibitors comprises both steroidal and nonsteroidal aldosterone synthase inhibitors, the later being most preferred.
Preference is given to commercially available aldosterone synthase inhibitors or those aldosterone synthase inhibitors that have been approved by the health authorities.
The class of aldosterone synthase inhibitors comprises compounds having differing structural features. For example, mention may be made of the compounds which are selected from the group consisting of the non-steroidal aromatase inhibitors anastrozole, fadrozole (including the (+)-enantiomer thereof), as well as the steroidal aromatase inhibitor exemestane. or, in each case where applicable, a pharmaceutically acceptable salt thereof. The most preferred non-steroidal aldosterone synthase inhibitor is the (+)-enantiomer of the hydrochloride of fadrozole (US patents 4617307 and 4889861) of formula
Figure imgf000065_0001
or, if appropriable, a pharmaceutically acceptable salt thereof.
A preferred steroidal aldosterone antagonist is eplerenone (cf. EP 122232 A) of the formula
Figure imgf000065_0002
or Spironolactone; or, in each case, if appropriable, a pharmaceutically acceptable salt thereof.
Aldosterone synthase inhibitors useful in said combination are compounds and analogs generically and specifically disclosed e.g. in US2007/0049816, in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to this publication. Preferred aldosterone synthase inhibitors suitable for use in the present invention include, without limitation 4-(6,7-dihydro- δH-pyiτoiop ^-climidazol-S-yO-S-methylbenzonitrile; 5-(2-chloro-4-cyanophenyl)-6,7-dthydro- 5H-pyrrolo[1 ^-cjimfdazole-δ-carboxylic acid (4-methoxybenzyl)methylamide; 4'-fluoro*6- (6.7,8,9-tetrahydro-5H-imidazo[1 ,5-a}azepin-5~yl)bipnenyl-3-carbonitrile; 5-(4-Cyano-2- methoxyphenyO-ΘJ-dihydro-δH-pyrroloti^-cJimidazole-S-carboxylic acid butyl ester, 4-(6,7- Dihydro-5H-pyrrolot1 ,2-c]imida2o!-5-yl)-2-methoxybenzonitnle; 5-(2-Chloro~4-cyanophenyl)- 6,7-dihydro-5f^pyrrok>[1 ,2-c]irnidazo}e-5-carboxyiic acid 4-fluorobenzyi ester; 5-(4-Cyano~2- trifluoromethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1.Σ-cJimidazole-δ-carboxylic acid methyl ester; 5-(4-Cyano-2-methoxyphenyl)*6.7-dihydro-5W-pyrrolo[1 ,2-c]imidazo}e-5-carix)xylic acid 2~isopropoxyethyl ester; 4-(6,7-Dihydro-5H-pyrrolo[1 ^-cJimidazol-δ-yO^-methylbenzonitrile; 4-(6,7-dihydro-5H-pyrroIo[1 ,2-c]imidazol-5-yi)-3-flucMObenzonitrile ; 4-(6,7-Dihydro-5H- pyrrolo[1,2-c]imidazol-5-yl)-2-methoxybenzonitrile; 3-Flυoro-4-(7-methylene-6,7-dihydro-5W- pyrrolo[1 ,2-c]imidazol-5-yl)benzonitrile; c/s-3-Fluoro-4-[7-(4-fluoro-benzyl)-5,6,7,8-tetrahydro- »midazo{1,5-a}pyrklin-5-yl}benzonitrile; 4'-Fluoro-6-(9-methyl-67,8,9-tetrahydro-5W- irnidazo[1 ,5-a}azepin-5-yl)biphenyl-3-carbonitrile; 4'-Fluoro-6-(9-methyl-6,7,8,9-tetrahydro- 5H-imidazo[1 ,5-a]azepin-5-yl)biphenyl-3-carbonitrile or in each case, the (R) or (S) enantiomer thereof; or if appropriable, a pharmaceutically acceptable salt thereof.
The term aldosterone synthase inhibitors also include compounds and analogs disclosed in WO2008/076860, WO2008/076336, WO2008/076862, WO2008/027284, WO2004/046145, WO2004/014914, WO2001 /076574.
Furthermore Aldosterone synthase inhibitors also include compounds and analogs disclosed in U.S. patent applications US2007/0225232, US2007/0208035, US2008/0318978, US2008/0076794, US2009/0012068, US20090048241 and in PCT applications WO2006/005726, WO2006/128853, WO2006128851 , WO2006/128852, WO2007065942, WO2007/116099, WO2007/116908, WO2008/119744 and in European patent application EP 1886695. Preferred aldosterone synthase inhibitors suitable for use in the present invention include, without limitation 8-(4-Fluorophenyl)-5l6-dihydro-8H-imida2x>[5,1-c1(1 ,41oxazine; 4-(5,6-Dfhydrσ-8H-imidazo(5,1-c][1 ,4]oxazin-8~yl)-2-fluorobenzonitriie; 4-(5,6- Dihydro-8H-imidazo[5, 1 -c}(1 ,4Joxazin~8-yl)-2,6-difluorobenzonitrile; 4~(5,6-Dihydro-8H- imidazo[5,1-c)(1 ,4Joxazin-8-yl)-2-methoxybenzonitriie; 3-(5,6-Dihydro-8H-imidazo[5,1-c}[1 ,4|oxazin-8-yl)benzonitrite; 4-(5,6-Dihvdro-8H-imidazo|;5,1-c}[1 ,4]oxazin-8-yl)phthalonitrile; 4- (8~(4~Cyanophenyl)-5,6-dihydro-8H-imidazo[5,1-c][1 ,4]oxazin-8-yl)benzonitrile; 4-(5,6- Dihydro-8H-imidazo{5,1-cl[1 ^joxazin-δ-yObenzonitrile^^S.β-Dthydro-ΘH-imidazofδ.i-clti ,4}oxazin-8-yl)naphthatene-1 -carbonitrtle; 8-[4-(1 H-Tetrazol-5-yl)phenyl1 -5,6-dihvdro-8H- imidazo(5,1-c][1 ,4}oxazine as developed by Speedel or in each case, the (R) or (S) enantiomer thereof; or if appropriable, a pharmaceutically acceptable salt thereof.
The term "endothelin receptor blocker" includes bosentan.
The term "CETP inhibitor" refers to a compound that inhibits the cholesteryl ester transfer protein (CETP) mediated transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL. Such CETP inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., U.S. Pat. No. 6,140,343). Examples include compounds disclosed in U.S. Pat. No. 6,140,343 and U. S. Pat. No. 6,197,786 (e.g. , [2R,4S]4-[(3,5-bis-trifluoromethyl-ben2yl)-methoxyc^rbonyl- amino)-2-ethyl-6-tr(flucM-omethyI- 3(4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (torcetrapib); compounds disclosed in U.S. Pat. No. 6,723,752 (e.g., (2R)-3-{{3-(4-Chloro-3-ethyl-phenoxy)-phenylH[3-(1 , 1 ,2,2- tetrafluoro-ethoxy)-phenyl]-methyl}-amino}- 1,1 ,1 -trifluoro-2-propanoO; compounds disclosed in U.S. patent application Ser. No. 10/807,838; polypeptide derivatives disclosed in U.S. Pat. No. 5,512,548; rosenonolactone derivatives and phosphate-containing analogs of cholesteryl ester disclosed in J. Antibiot, 49(8): 815- 816 (1996), and Bioorg. Med. Chem. Lett.; 6:1951-1954 (1996), respectively. Furthermore, the CETP inhibitors also include those disclosed in WO2000/017165, WO2005/095409 and WO2005/097806.
A prefered PDE5 inhibitor is Sildenafil.
Second agent of particular interest include Endothelin antagonists, renin inhibitors, angiotensin Il receptor antagonists, calcium channel blockers, diuretics, antidiabetic agents such as DPPIV inhibitors, and aldosterone synthase inhibitors.
EXEMPUFJCATION OF THE INVENTION:
All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21 ). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples,
The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art. The compounds in the example 5-1 to 15-3 have been found to have IC50 values in the range of about 0.01 nM to about 10,000 nM for NEP.
The conditions for measuring the retention times are as follows:
HPLC condition A:
Column: INERTSIL C8-3, 3μm x 33mm x 3.0mm at 40°C Flow rate: 2 ml / min
Mobile phase: A) 5 mM aqueous HC00NH4, B) MeOH / CH3CN (1 / 1 , v / v)
Gradient: linear gradient from 5% A to 95% B in 2 min
Detection: DAD-UV at 200-400 nm
HPLC condition B:
Column: INERTSIL C8-3. 3μm x 33mm x 3.0mm at 4O°C
Flow rate: 2 mi / min
Mobile phase: A) 5 mM aqueous HCOONH4, B) MeOH / CH3CN (1 / 1, v / v)
Gradient: linear gradient from 40% A to 95% B in 2 min
Detection: DAD-UV at 200-400 nm
HPLC condition C:
Column: INERTSIL C8-3, 3μm x 33mm x 3.0mm at 40 °C
Flow rate: 2 ml / min
Mobile phase: A) (5 mM NH4 +HCOO-)/water, B) MeOH / CH3CN (1 / 1 , v / v)
Gradient: linear gradient from 5 to 95% B in 2 min
Detection: DAD-UV at 200-400 nm
HPLC condition D:
Column: INERTSIL C8-3, 3μm x 33mm x 3.0mm at 40 °C
Flow rate: 2 ml / min
Mobile phase. A) 0.1% aqueous Formic acid, B) MeOH / CH3CN (1 / 1. v / v)
Gradient: linear gradient from 5% B to 95% B in 2 min
Detection: DAD-UV at 200-400 nm
HPLC condition E:
Coiumn: lnertsil C8-3, 3μm x 33mm x 3.0mm at 40 °C
Flow rate: 2 ml / min
Mobile phase: A) methanol / acetonitrile (1 / 1 , v / v), B) 5 mM aquesous HCOONH4
Gradient: linear gradient from 40% B to 95% A in 2 min
Detection: UV at 214 nm The relative stereochemistry was determined using two dimensional NMR. Under the reaction condition, it would be unexpected that the stereocenter bearing the bisphenyl- methyl group racemize. Therefore, the absolute stereochemistry was determined based on the relative stereochemistry and the absolute stereochemistry of the stereocenter bearing the bisphenyl-methy! group.
Example 1-1 : Synthesis of (R)-4-(1»{biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4- oxobυtanoic acid
Figure imgf000069_0001
intermediate 2
To (/?)-ethyl-4-(biphenyf-4~yl)-3-(tert-butσxycarbonylamino)butanoate (230.1 mg, 0.600 mmol) is added a solution of HCI in 1 ,4-dioxane (3.00 mL, 12.00 mmol) at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to give {/^-S-amtno-ΦbtphenyM-yl-butyric acid ethyl ester hydrochloride. A solution of (/?)-3-amino- 4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride, succinic anhydride (72.1 mg, 0.720 mmol) and DIPEA (0.126 mL, 0.720 mmof) in cfichloromethane (4 mL) is allowed to stir for 1 hour. The reaction is quenched with 10% aqueous citric acid and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on CN-modified silica gel (elυent: heptane/EtOAc « 100:0 to 0:100) and by RP-HPLC (SυnFire C18, H2O(0.1%TFA)/CH3CN) to give (R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ytamino)-4- oxobutanoic acid (148.2 mg). HPLC retention time = 1.64 minutes (condition A); MS (m+1) = 384.1; 1H NMR (400 MHz1 ACETONITRILE-d3) δ ppm 1.21 (t, J=7.07 Hz, 3 H) 2.31 - 2.39 (m. 2 H) 2.40 - 2.56 (m, 4 H) 2.77 - 2.92 (m. 2 H) 4.08 (q,
J-7.24 Hz, 2 H) 4.33 - 4.48 (m. 1 H) 6.62 (d, J-8.3A Hz, 1 H) 7.30 (d, J=8.08 Hz, 2 H) 7.32 - 7.39 (m, 1 H) 7.41 - 7.49 (m, 2 H) 7.54 - 7.60 (m. 2H) 7.60 - 7.67 (m, 2 H) 10.02 (br. s., 1 H).
Example 1«2: Synthesis of (RH^I^S'^hlorobiphenyM-yO^thøxy-A-oxobutan^- ylaminoM-oxøbutanofc acid
Figure imgf000070_0001
A solution of (R)-ethyl 3~amino-4-(3'-chlorobiphenyl~4-yl)butanoate hydrochloride (400 mg, 1.13 mmol), succinic anhydride (136 mg, 1.36 mmol) and DIPE=A (0.237 mL, 1.36 mmol) in dichloromethane (5 mL) is allowed to stir for 2.5 hours. The reaction is quenched with 1 M aqueous HCI and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(3'- chlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (255 mg). HPLC retention time - 1.15 minutes (condition B); MS (m+1) ~ 418.0; 1 H NMR (400 MHz, CHLOROFORM-cO δ ppm 1.29 (t, J = 7.08 Hz1 3 H) 2.46 - 2.58 (m, 4 H) 2.64 ~ 2.67 (m, 2 H) 2.87 (A of ABX, Jsb « 13.6 Hz, JM * 7.8 Hz, 1 H) 2.99 (B of ABX, Jβb - 13.6 Hz, Λx - 6.6 Hz, 1 H) 4.12 - 4.24 (m, 2 H) 4.47 - 4.55 (m, 1 H) 6.50 (br d, J « 8.8 Hz, 1 H) 7.24 - 7.37 (m, 4 H) 7,43 - 7.46 (m, 1 H) 7.48 - 7.52 (m, 2H) 7.55 - 7.56 (m, 1 H). Chiral HPLC retention time = 3.59 min. Column: Daicel CHIRALPAK AD-H (4.6x100mm); flow rate « 1 mi/min.; eluent: EtOH(containing 0.1% TFA)/heptane = 4/6.
Following compounds are prepared using similar procedure as described in example 1-2:
Figure imgf000070_0002
Figure imgf000071_0001
Figure imgf000072_0001
Example 1-3: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J ~ 7.2 Hz, 3 H) 1.86 - 1.97 (m, 2 H) 2.25 - 2.28 (m, 2 H) 2.34 (t, J ~ 7.0 Hz, 2 H) 2.50 (A of ABX, JM ~ 16.2 Hz, Jax = 5.6 Hz, 1 H) 2.56 (B of ABX, Jab - 16.2 Hz, Jbx « 5,1 Hz, 1 H) 2.88 (A of ABX, JΛ ~ 13.6 Hz1 Jaκ = 7.8 Hz1 1 H) 2.98 (B of ABX1 Λb s 13.6 Hz, Jbx * 7.1 Hz, 1 H) 4.12 - 4.23 (m, 2 H) 4.50 - 4.58 (m, 1 H) 6.32 (br d, J ~ 8.8 Hz, 1 H) 7.25 - 7.37 (m, 4 H) 7.43 - 7.46 (m, 1 H) 7.49 - 7.52 (m, 2 H) 7.55 - 7.56 (m, 1 H). Exampte 1-4; 1 H NMR (400 MHz1 CHLOROFORM-d) 6 ppm 1.29 (t, J = 7.1 Hz, 3 H) 1.86 - 1.97 (m, 2 H) 2.26 - 2 28 (m, 2 H) 2,34 (t, J = 7.0 Hz1 2 H) 2,54 (A of ABX, JΛ « 16.1 Hz, J8x - 5.6 Hz, 1 H) 2.58 (B of ABX, Jab * 16.1 Hz, J^ - 5.2 Hz, 1 H) 2.88 (A of ABX1 Jab - 13.5 Hz, Jax = 7.6 Hz, 1 H) 2.97 (B of ABX, Jab « 13.5 Hz, J6x ~ 7.0 Hz1 1 H) 3.78 (s, 3 H) 4.12 - 4.23 (m, 2 H) 4.50 - 4,59 (m, 1 H) 6,34 (far d, J « 8,6 Hz, 1 H) 6.88 - 6.91 (m, 1 H) 6.96 - 7.04 (m, 2 H) 7.23 (d, J ~ 8.3 Hz1 2 H) 7.44 - 7.47 (m, 2 H),
Example 1-5: 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J = 7.1 Hz, 3 H) 1.86 - 1.97 (m, 2 H) 2.25 - 2 36 (m, 4 H) 2.49 - 2.61 (m, 2 H) 2.88 (A of ABX, Jab = 13.6 Hz1 Jax =
7.6 Hz, 1 H) 2.97 (B of ABX, J36 = 13.6 Hz, Jbx = 6.8 Hz, 1 H) 3,79 (s, 3 H) 4.12 - 4.23 (m, 2 H) 4.50 - 4.59 (m, 1 H) 6.34 - 6.36 (m. 1 H) 6.89 (d, J = 8.6 Hz, 1 H) 7.21 - 7.28 (m, 3 H) 7.43 (d, J = 8,1 Hz1 2 H),
Example 1-6: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J = 7.1 Hz, 3 H) 2.47 - 2.67 (m, 6 H) 2.89 (A of ABX. Jab - 13,7 Hz1 J3, - 7.8 Hz, 1 H) 3.00 (B of ABX, Jab = 13.7 Hz, J5x = 6.7 Hz, 1 H) 4.12 - 4.24 (m, 2 H) 4.49 - 4.57 (m, 1 H) 6.51 (br d, J - 8.6 Hz, 1 H) 6.97 -
7.07 (m, 2 H) 7.24 - 7.26 (m, 2 H) 7,36 - 7.43 (m, 3 H).
Example 1-7: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J * 7.1 Hz, 3 H) 2,23 - 2.27 (m, 2 H) 2,34 - 2.38 (m. 2 H) 2.40 - 2.47 (m, 2 H) 2.77 (d, J = 6.6 Hz, 2 H) 3,99 - 4.06 (m, 2 H) 4.21 - 4.30 (m, 1 H) 7.14 - 7,19 (m, 1 H) 7,29 (d, J = 8.4 Hz, 2 H) 7.46 - 7.52 (m, 3 H) 7,63 (d, J * 8.4 Hz, 2 H) 7,91 (d, J » 8.3 Hz, 1 H) 12.04 (s, 1 H).
Example 1-8: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.41 - 2.45 (m, 2 H) 2.50 - 2.64 (m, 4 H) 2.81 - 2,87 (m, 1 H) 2.95 - 3.00 (m, 1 H) 4.49 - 4.56 (m, 1 H) 5.12 (A of AB, J = 12.1 Hz, 1 H) 5.18 (B of AB, J = 12.1 Hz1 1 H) 6.39 (d, J = 8.1 Hz, 1 H) 7,18 - 7.54 (m, 13 H).
Example 1-9: 1H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO-d6): δ ppm 1.22- 1.25 (t, J«7.07 Hz1 3H), 2.61-2.63 (m, 2H)1 2.91 (d, J=7.07 Hz, 2H)1 4,09 (q, J=7.07 Hz1 2H), 4.52-4.59 (m, 1 H), 7.32-7.34 (m, 3H), 7.04 (t. J=7.83 Hz, 1H)1 7.52-7.56 (m, 3H), 7.59 (t, J-2.02 HZ, 1 H).
Example 1-10: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.03 - 2,13 (m, 2 H)1 2,44 (t, J=6,3 Hz, 2 H), 2.64 (t, J=6.6 Hz, 2 H), 2.70 (dd, J«16.2, 5,6 Hz, 1 H), 2.78 (dd, J=16.2, 5.1 Hz, 1 H), 2.83 - 2.98 (m, 5 H), 3.04 (dd, J-13.9, 6.8 Hz, 1 H)1 4.67 - 4.69 (m, 1 H), 6.51 (d, J-8.8 Hz1 1 H), 6.79 (dd, J=B.1, 2.3 Hz1 1 H), 6.90 (d, J=1.8 Hz, 1 H), 7.18 (d, J=8.1 Hz1 1 H)1 7.26 - 7.31 (m. 3 H)1 7.34 (t, J=7.7 Hz, 1 H), 7.43 (di, J=7.3, 1.5 Hz, 1 H), 7.49 (d, J=8.1 Hz, 2 H), 7.54 (t, J=1.8 Hz, 1 H)1 9.34 (br. s., 1 H).
Example 1-11: Synthesis of (f?)-4-<1-{2',5*-dichlorobiphenyl-4-yl)-4*ethoxy-4-oxobutan- 2-ylamino)-4-oxobutanoic acid
Figure imgf000074_0001
To (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(2l,5'-dichlorobiphenyl-4-yl)butanoate (1.09 g, 2,33 mmol) is added a solution of 4 M HCI in 1 ,4-dioxane (5.81 ml_, 23.3 mmol) at room temperature. After stirring for 2 hours, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 3-amino-4-(2',5'-dichlorobipheny(-4-yl)butanoate hydrochloride. Next, a solution of the product, succinic anhydride (280 mg, 2.80 mmol) and DIPEA (0.489 mL, 2.80 mmol) in dichloromethane (15 mL) is allowed to stir for 2 hours. The reaction is quenched with 1 M aqueous HCI and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1~(2(,5'-dichlorobiphenyl-4-yl)-4~ethoxy-4-oxobutan-2-ylamino)-4- oxobutanoic acid (553 mg) as a white solid; HPLC retention time ~ 1,02 minutes (condition B); MS (m+1) ~ 452.14; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J = 7.2 Hz, 3 H) 2.47 - 2.67 (m, 6 H) 2.89 (A of ABX, JΛ = 13.7 Hz1 J3x = 7.8 Hz, 1 H) 3.00 (B of ABX, J#> « 13.7 Hz, Jbκ a 6.7 Hz1 1 H) 4.12 - 4.24 (m, 2 H) 4.49 - 4.57 (m, 1 H) 6.53 (br d, J= 8.8 Hz, 1 H) 7.23 - 7.26 (m, 3 H) 7.32 - 7.40 (m, 4 H).
Following compounds are prepared using similar procedure as described in example 1-11 :
Figure imgf000074_0002
Figure imgf000075_0001
Figure imgf000076_0001
Example 1-12: 1H NMR (400 MHz1 DMSO-d*) δ ppm 0.87 (t, J=7.5 Hz, 3 H), 1.49 • 1.61 (m, 2 H), 2.22 - 2,29 (m. 2 H), 2.32 - 2.39 (m, 2 H), 2.45 (dd, J=6,9, 3.4 Hz1 2 H)1 2.78 (dt J=6.6 Hz1 2 H)1 3.94 (t, J=6.6 Hz1 2 H)1 4.21 - 4.33 (m, 1 H)1 7.29 (d, J-8.3 Hz, 2 H), 7.37 - 7.42 (m, 1 H), 7.47 (t. J=7.8 Hz1 1 H)1 7.58 - 7.65 (m, 3 H). 7.69 (t, J=1.9 Hz, 1 H)1 7.92 (d, J=8.3 Hz, 1 H).
Example 1-13: 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94 (t, J=7.3 Hz, 3 H). 1.32 - 1.44 (m, 2 H), 1 ,56 - 1.67 (m, 2 H), 2.43 - 2.59 (m, 4 H), 2.65 (t, J=6.4 Hz, 2 H), 2.85 (άά, J=13.6, 8.1 Hz, 1 H), 2,99 (dd, J=13.6, 6.6 Hz, 1 H), 4.03 - 4.18 <m, 2 H), 4.43 - 4.56 (m, 1 H)1 6.57 (d, J=8.6 Hz. 1 H), 7.25 (d, J=8.3 Hz1 2 H), 7.28 - 7.32 (m, 1 H)1 7.35 (t, J-7.7 Hz, 1 H), 7.41 - 7.46 (m, 1 H), 7.48 (d, J=8.1 Hz, 2 H), 7.55 (t, J=1.8 Hz, 1 H).
Example 1-14: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.17 (S1 3 H), 2.44 (t, J=6.2 Hz, 2 H)1 2.48 - 2.57 (m. 1 H)1 2.57 - 2.73 (m, 3 H), 2.87 (dd, J=13.6, 7.6 Hz, 1 H), 2.98 (dd, J=13.9, 7.1 Hz, 1 H), 4,47 - 4.58 (m. 1 H)1 4,84 (s, 2 H), 6,32 (d, J=8.6 Hz, 1 H), 7.23 (d, J=8.1 Hz, 2 H), 7.30 (d, 1 H), 7.35 (t, J=7.7 Hz, 1 H). 7.44 (d, J=7.3 Hz, 1 H), 7.49 (d, J=8.1 Hz, 2 H), 7,54 (s, 1 H). Example 1-15: 1 H NMR (400 MHz1 CHLOROFORM-d) δ ppm 2.48 - 2.59 {m, 3 H). 2.61 - 2.71 (m, 3 H), 2.91 - 3.06 (m, 8 H), 4.53 - 4.63 (m, 1 H)1 4.67 (d. J=14.7 Hz, 1 H), 5.03 (d, J=14.7 Hz, 1 H), 7.30 (dt, J-7.8, 1.8 Hz, 1 H)1 7,32 - 7.38 (m, 3 H)1 7.45 (dt, J=7.6. 1.5 Hz1 1 H)1 7.50 (d, J=8.1 Hz, 2 H), 7.55 (t, J=1.8 Hz1 1 H), 8.08 (d, J=9.3 Hz1 1 H).
Example 1-16: 1H NMR (400 MHz1 DMSOd6) δ ppm 2.20 - 2.32 (m, 2 H), 2.32 - 2.41 (m, 2 H), 2.42 - 2.50 (m, 1 H)1 2.57 <dd, J=15.4, 5.6 Hz, 1 H), 2.80 (d. J=36.1 Hz1 2 H), 3.15 (br. s., 2 H)1 3.31 - 3.50 (m, 4 H), 3.52 - 4.05 (m, 4 H), 4.25 - 4.40 (m, 3 H). 7.31 (d, J=8.3 Hz, 2 H)1 7.39 - 7.43 (m, 1 H), 7.48 (t. J=7.8 Hz, 1 H), 7.60 - 7.67 (m, 3 H), 7.70 (t, J=1.8 Hz, 1 H), 8.02 (d, J-8.6 Hz, 1 H), 10.06 (br. s., 1 H), 12.17 (br. s., 1 H).
Example 1-17: Synthesis of (R)-4-(1-(5'-chloro-2'-fluorobiphenyJ-4-yl)-4-ethoxy-4- oxobutan-2«ylamino)-4-oκobutanoic acid
Figure imgf000077_0001
A solution of (R)-ethyl 3-amino-4-(5'-chloro-2'-fluorobiphenyl-4-yi)butanoate hydrochloride (293 mg, 0.777 mmol), succinic anhydride (93 mg, 0.932 mmoi) and DIPEA (0,204 mL, 1.165 mmol) in dichloromethaπe (4 mL) is allowed to stir for 1.5 hours. The reaction is quenched with 1 M aqueous HCI and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(5'-chloro-2'-f}uorobfphenyl-4-yl)-4-ethoxy-4-oxobυtan-2-ylamino)-4-oxobutanoic acid (294 mg). HPLC retention time = 1.03 minutes (condition B); MS (m+1) - 436.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J = 7.07 Hz, 3 H) 2.46 - 2,58 (m, 4 H) 2,64 - 2.68 (rn, 2 H) 2.87 (A of ABX, Jab « 13.64 Hz, Ja* = 7.83 Hz, 1 H) 2.99 (B of ABX, J^0 = 13.64 Hz, Λx ~ 6.57 Hz1 1 H) 4.11 - 4,22 (m, 2 H) 4.47 - 4.56 (n% 1 H) 6.60 (br d, J = 8.59 Hz, 1 H) 7.05 - 7.10 (m, 1 H) 7.23 - 7.27 (m, 3 H) 7.39 - 7.41 (m, 1 H) 7.44 - 7.46 (m. 2H). Following compounds are prepared using similar procedure as described in example 1-17:
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0002
Example 1-20: 1H NMR (400 MHz, CDCI3) S ppm 1.15 (t, J = 7.07 Hz, 3 H), 2.24-2.34 (m, 4 H), 2.74 (dd, J ~ 8.59, 13.39 Hz)1 2.88 (dd, J = 6.32, 13.39 Hz)1 3.34 (s, 3H), 3.75 (d, J = 2.78 Hz, 1 H), 4.04 (dd, J = 7.07, 13,89 Hz, 2 H), 4.33-4.43 (m, 1 H), 7.31 (d, J « 8.08 Hz, 2 H), 7 38-7.43 (m, 1 H), 7.48 (t, J = 7.83 Hz1 1 H), 7,63 (d, J = 3.34 Hz)1 7.71 (t, J = 1.77 Hz, 1 H), 7.95 (d, J = 9.35 Hz, 1 H).
Example 2-1: Synthesis of (R)-3-(3-carboxy-propionyiamino)«4--<4'-fluoro-biphenyl-4- yl)-butyric acid ethyl ester
Figure imgf000082_0001
A mixture of (R)-4-(1-(4-bromopheπyi)-4~ethoxy-4-oxobutan-2-yiamϊno)-4-oxobυtanoic acid (50 mg, 0.129 mmol), 4-fluorophenylboronic acid (27.2 mg, 0.194 mmof), Pd(Ph3P)4 (14.96 mg, 0.013 mmol) and aqueous Na2CQ3 (0.129 nriL, 0.259 mmol) in toluene (1 ml) is allowed to stir at 95 °C under nitrogen. After stirring for 13 hours, the solution is cooled to ambient temperature and then quenched with aqueous 1 M HCI. The products are extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN), and then lyophilized to give (R)-3-(3-carboxy-propionylamino)-4-(4'-fluoro- biphenyt-4-yl)-butyric acid ethyl ester (29.2 mg). HPLC retention time ~ 1.26 minutes (condition B); MS (m+1) = 402.2; 1H NMR (400 MHz, CHLOROFORM-cQ δ ppm 1.29 (t, J ~ 7 Hz, 3 H) 2.47 - 2.67 (m, 6 H) 2.87 (A of ABX, Jab - 13.7 Hz, Jax = 7.9 Hz, 1 H) 2.99 (B of ABX, Jab = 13.7 Hz1 Jbx ~ 6.6 Hz1 1 H) 4.12 ~ 4.23 (m, 2 H) 4.47 - 4.55 (m, 1 H) 6.52 (br d, J = 8.6 Hz, 1 H) 7.08 - 7.14 (m, 2 H) 7.24 (d, J = 8.4 Hz1 2 H) 7.46 - 7.55 (m, 4 H).
Following compounds are prepared using similar procedure as described in example 2-1 :
Figure imgf000082_0003
(condition)
Pd(PPh3)4, p-chlorophenylboronic
Cl acid, aq. 2M Na2CO3,
Example 2-
1 49 min. (B) 418.1 2 ft (RH-(I -(4-
O * mophenyl)-4-
U >*% bro
H 0 ethoxy-4-oxobutan-2- ylamino)-4- oxobυtanoic acid
Pd(PPh3J4, m-fiuorophenylboronic
F acid, aq. 2M Na2CO3,
Example 2- (R)-ethyl A-(A-
1.24 min. (B) 416.1 3 bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan oate.
Pd(PPha)A, o-fluorophenylboronic acid, aq. 2M Na2CO3,
Example 2- (R)-ethyl 4-(4-
1.25 min. (B) 416.1 4 J? - bromopheπyl)-3-(4- methoxy-4- oxobutanam ido) bυtan oate.
Pd(PPh3)4, o-chlorophenyiboronic acid, aq. 2M Na2CO3.
Example 2- (R)-ethyl 4-(4-
1.33 min. (B) 432.1 5 . ϊ f 0 bromtrphenyl)-3-(4-
: ; methoxy-4- oxobutanamido)butan oate.
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Example 2-2: 1H NMR (400 Mf-te, CHLOROFORM-d) δ ppm 1.29 (t, J » 7 Hz, 3 H) 2.47 ~ 2.67 (m, 6 H) 2.84 - 3.02 (m. 2 H) 4.12 - 4.24 (m, 2 H) 4.47 - 4.55 (m, 1 H) 6.52 (br d, J * 9.3 Hz, 1 H) 7.24 - 7.26 (m, 2 H) 7.39 - 7.41 (m, 2 H) 7.48 - 7.51 (m, 4 H). Example 2-3: 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J = 7 Hz, 3 H) 2.43 - 2.65 <m, 6 H) 2.84 - 3.02 (m, 2 H) 3.67 (s, 3 H) 4.12 - 4.23 (m, 2 H) 4.47 - 4.55 (m, 1 H) 6.30 (br d, J ~ 8.6 Hz, 1 H) 7.00 - 7.05 (m, 1 H) 7.26 - 7.29 (m, 3 H) 7.34 - 7.41 (m, 2 H) 7.51 (d, J= 8.3 Hz, 2 H).
Example 2-4: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J - 7 Hz, 3 H) 2.44 - 2.65 (m, 6 H) 2.85 - 3.02 (m. 2 H) 3.67 (s, 3 H) 4.11 - 4.23 (m, 2 H) 4.48 - 4.56 (m, 1 H)
6.30 (br d, J * 9.6 Hz, 1 H) 7.11 - 7.22 (m. 2 H) 7.25 - 7.33 (m, 3 H) 7.40 - 7.45 (m, 1 H) 7.48 - 7.50 (m, 2 H).
Example 2-5: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J = 7.2 Hz, 3 H) 2.44 -
2.65 <m. 6 H) 2.86 - 3.02 (m, 2 H) 3.68 (s, 3 H) 4.12 - 4.23 (m, 2 H) 4.49 - 4.57 (m, 1 H)
6.31 (br (J1 J a 8.8 Hz, 1 H) 7.24 - 7.34 (m, 5 H) 7.37 - 7.39 (m, 2 H) 7.45 - 7.47 (m, 1 H).
Example 2-6: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J « 7 Hz, 3 H) 2.44 -
2.66 (m, 6 H) 2.84 - 3.01 (m, 2 H) 3.68 (s, 3 H) 3.81 (s, 3 H) 4.11 - 4.23 (m, 2 H) 4.48 - 4.56 (m, 1 H) 6.26 (br d, J = 8.8 Hz1 1 H) 6.97 - 7.04 (m, 2 H) 7.22 (d, J = 8.1 Hz, 2 H) 7.29 - 7.33 (m, 2 H) 7.46 - 7.48 (m, 2 H).
Example 2-7: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J - 7.1 Hz, 3 H) 2.26 (β, 3 H) 2.44 - 2.69 (m, 6 H) 2.85 - 3.01 (m, 2 H) 3.68 (S1 3 H) 4.12 ~ 4.23 (m, 2 H) 4.48 - 4.57 (m, 1 H) 6.30 (br d, J = 8.6 Hz, 1 H) 7.21 - 7.26 (m, 8 H).
Example 2-8: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J » 7.2 Hz, 3 H) 2.44 - 2.69 (m, 6 H) 2.86 - 3.03 (m, 2 H) 3.68 (s, 3 H) 4.12 - 4.23 (m, 2 H) 4.48 - 4.57 (m, 1 H) 6.31 (br d, J = 8.8 Hz, 1 H) 6,90 - 7.01 (m, 1 H) 7.05 - 7.08 (m, 1 H) 7.25 - 7.27 (m, 2 H) 7.36 - 7.43 (m, 3 H).
Example 2-9: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J = 7.2 Hz, 3 H) 2.41 - 2.65 (m, 9 H) 2.84 - 3.00 (m. 2 H) 3.67 (s, 3 H) 4.11 - 4.23 (m, 2 H) 4.47 - 4.55 (m, 1 H) 6.29 (br d, J * 8.9 Hz. 1 H) 7.16 - 7.39 (m, 6 H) 7.50 - 7.53 (m, 2 H).
Example 2-10: 1H NMR (400 MHz1 CHLOROFORM-c/) δ ppm 1.29 (t, J - 7.2 Hz, 3 H) 2.43 - 2.65 (m, 6 H) 2.84 - 3.02 (m, 2 H) 3.67 (s, 3 H) 4.12 - 4.23 (m, 2 H) 4.46 - 4.55 (m, 1 H) 6.33 (br d, J - 8,8 Hz. 1 H) 6.76 - 6.80 <m, 1 H) 7.06 - 7.12 (m, 2 H) 7.26 - 7.27 (m, 2 H) 7. 48 (d, J = 8.0 Hz. 2 H).
Example 2-11 : 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 - 1.30 (m, 6 H) 2.44 -
2.57 (m, 4 H) 2.62 - 2.74 (m, 4 H) 2.84 ~ 3.00 (m, 2 H) 3.67 (β, 3 H) 4.13 - 4.23 (m, 2 H)
4.47 ~ 4.55 (m, 1 H) 6.30 (br d, J = 7.6 Hz, 1 H) 7.17 - 7.26 (m, 3 H) 7.33 - 7.41 (m, 3 H) 7. 52 (d, J = 7.8 Hz1 2 H).
Example 2-12: 1H NMR (400 MHz, CHLOROFORM-cf) δ ppm 1.30 (t, J = 7.1 Hz, 3 H) 2.41 - 2.65 (m, 6 H) 2.67 - 2.92 (m, 1 H) 3.00 - 3.05 (m. 1 H) 3.68 (s, 3 H) 4.14 - 4,22 (m, 2 H)
4.48 - 4.56 (m. 1 H) 6.33 (br d, J = 8.6 Hz. 1 H) 7.32 (d, J = 8.3 Hz, 2 H) 7.56 - 7.62 (m, 3 H) 7.89 - 7.91 (in, 1 H) 8.18 - 8.20 (m, 1 H) 8.44 (t, J ~ 8.0 Hz, 1 H).
Example 2-13. 1H NMR (400 MHz, CHLOROFORM-^ δ ppm 1.29 (t, J - 7.2 Hz1 3 H) 2.44 - 2,65 (m, 6 H) 2.86 - 2.91 (m, 1 H) 2.98 ~ 3.03 (m. 1 H) 3.67 (s, 3 H) 4,13 - 4.22 (m, 2 H) 4.47 - 4.56 (m. 1 H) 6.33 (br d, J ~ 8.8 Hz, 1 H) 7.29 (d, J = 8.2 Hz, 2 H) 7.53 (d, J ~ 8.2 Hz, 2 H) 7.56 - 7.60 (m, 2 H) 7.75 (d, J = 7.6 Hz, 1 H) 7.81 (s, 1 H).
Example 2-14: 1H NMR (400 MHz. CHLOROFORM-cf) δ ppm 1.28 (t. J ~ 7.2 Hz, 3 H) 2.43 - 2.65 (m, 6 H) 2.84 - 2,89 (m, 1 H) 2,96 - 3.01 (m, 1 H) 3.67 (s, 3 H) 3.86 (s, 3 H) 4.11 ~ 4.23 (m, 2 H) 4.47 - 4,55 (m, 1 H) 6,30 (br d, J = 8.8 Hz, 1 H) 6.87 - 6.90 (m, 1 H) 7.10 -
7.11 (m, 1 H) 7.15 - 7.17 (m, 1 H) 7.24 - 7,26 (m, 2 H) 7,34 (t, J = 7.8 Hz, 2 H) 7.51 - 7.53 (m, 2 H).
Example 2-15: 1H NMR (400 MHz, CHLOROFORM-*/) δ ppm 1.29 (t, J = 7.1 Hz, 3 H) 2.43 -
2.58 (m, 4 H) 2.61 - 2.65 (m, 2 H) 2.84 - 2.91 (m, 1 H) 2.98 - 3.03 (m. 1 H) 3.68 (s, 3 H)
4.12 - 4.24 (m, 2 H) 4.47 - 4.55 (m, 1 H) 6.34 (br d, J = 8.8 Hz, 1 H) 7.30 (d, J = 8.1 Hz1 2 H) 7.50 (d, J ~ 8.1 Hz1 2 H) 7.51 - 7.63 (m, 2 H) 7,78 - 7.81 (m. 1 H) 7.85 (br s, 1 H).
Example 2-16: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J ~ 7.1 Hz, 3 H) 2.43 - 2.57 (m, 4 H) 2.61 - 2.64 (m, 2 H) 2.87 (A of ABX1 Jab = 13.6 Hz1 J8x = 7.8 Hz1 1 H) 2.99 (B of ABX, J8b » 13.6 Hz, Jbx = 6.6 Hz, 1 H) 3.68 (S1 3 H) 4.12 - 4.23 (m, 2 H) 4.46 - 4.55 (m, 1 H) 6.34 (br d, J - 8.6 Hz, 1 H) 7.05 (dt, J = 8.3 and 2.0 Hz, 1 H) 7.15 - 7.19 (m, 1 H) 7.26 - 7,28 (m, 3 H) 7.35 ~ 7.36 (m, 1 H) 7,45 (d, J - 8.1 Hz. 2 H). Exampte 2-17: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J = 7.1 Hz1 3 H) 2.43 - 2.69 (m, 6 H) 2.90 (A of ABX1 Jab β 13.6 Hz, J9, = 7.8 Hz1 1 H) 2.99 (B of ABX, Jab = 13.6 Hz1 Jbx * 6.8 Hz, 1 H) 3.68 (s, 3 H) 4.12 - 4.23 (m. 2 H) 4.49 - 4.57 (m, 1 H) 6.31 (bf d, J « 8.6 Hz, 1 H) 7.20 - 7.26 (m. 4 H) 7.32 (α\ J ~ 7.6 Hz. 1 H) 7.44 - 7.47 (m. 1 H) 7.53 - 7.57 <m, 1 H) 7.73 (d, J « 7.6 Hz, 2 H).
Example 2-18: 1H NMR (400 MHz, CHLOROFORM-o) δ ppm 1.29 (t. J « 7.2 Hz, 3 H) 2.44 - 2.65 (m, 6 H) 2.91 (A of ABX, Jaύ = 136 Hz, Jm - 7.8 Hz. 1 H) 3.01 (B of ABX, Jab ~ 13.6 Hz, Jbx = 6.6 Hz, 1 H) 3.68 (s, 3 H) 4.12 - 4.24 (m, 2 H) 4.48 - 4.57 (m, 1 H) 6.34 (br d, J = 8.6 Hz, 1 H) 7.32 (d, J = 8.1 Hz, 2 H) 7.41 - 7.56 (m, 2 H) 7.62 - 7.66 (m, 1 H) 7.75 - 7.77 (m, 1 H) 7.81 - 7.84 (m, 2 H).
Example 2-19: 1H NMR (400 MHz. CHLOROFORM-cf) δ ppm 1.28 (\, J ~ 7 Z Hz, 3 H) 1.35 (t, J β 6.9 Hz, 3 H) 2.44 - 2.53 (rti, 4 H) 2.44 - 2.53 (m. 4 H) 2.86 (A of ABX, JΛ ~ 13.6 Hz, J8x = 8.1 Hz, 1 H) 2.98 (B of ABX, J3t> = 13.6 Hz, Jbx « 6.1 Hz, 1 H) 3.67 (s, 3 H) 3.99 - 4.23 (m, 4 H) 4.48 - 4.56 (m, 1 H) 6.27 (br d. J ~ 8 6 Hz1 1 H) 6.94 - 7.04 (m, 2 H) 7.20 - 7.22 (m, 2 H) 7.27 - 7.33 (m, 2 H) 7.41 - 7.52 (m, 2 H).
Example 2-20: 1H NMR (400 MHz1 CHLOROFORM-c/) δ ppm 1.28 (t, J - 7.2 Hz, 3 H) 1.43 (s, 9 H) 2.36 -2.56 (m, 6 H) 2 84 - 3.01 (m, 4 H) 4.11 - 4.22 (m, 2 H) 4.47 - 4.56 (m, 1 H) 6.30 - 6.35 (m, 1 H) 7.25 - 7.27 (m, 2 H) 7.51 - 7 .54 (m, 2 H).
Example 2-21: Synthesis of (R)-4-(4-βthoxy-1-{5'-fluoro-2'-methoxybiphenyl-4-ylH- oxobutan«2-ylamino)-4-oxobutanoic acid
Figure imgf000090_0001
To a solution of (R)-tert-butyl 4-(1-(4-bromophenyl)~4-ethoxy-4-oxobυtan-2-ylamino)-4- oxobutanoate, intermediate 9, (100 mg, 0.23 mmol) and 5-fluoro-2-methoxyphenylbσronic acid (57.6 mg, 0.34 mmol) in toluene (1 mL) and EtOH (0.1 ml) is added Pd(PPh3),, (26.1 mg, 0.023 mmol) and Na2CO3 (47.9 mg, 0.45 mmol). After stirring at 95 °C under nitrogen for 18 hours, the solution is cooled to ambient temperature and then quenched with aqueous 1 M HCI. The crude is diluted with ethyf acetate, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc = 100:0 to 30:70) to give (R)-tert-butyl 4-(4-ethoxy-1-(5'-fluoro-2'-methoxybiphenyl-4-yi)-4-oxobutan-2- ylamino)-4-oxobutanoate (65 mg), HPLC retention time = 1.44 minutes (condition B); MS (m+1) a 488.3; 1H NMR (400 MHz, CHLOROFORM-cf) δ ppm 1.32 (t. J=7.1 Hz, 3 H) 1.48 (s, 9 H) 2.41 - 2.48 (m, 2 H) 2.51 - 2.63 (m, 4 H) 2.90 (dd, J=13.6, 6 Hz, 1 H) 3 02 (dd, J=13.6, 6 Hz1 1 H) 3.81 (S, 3 H) 4.14 - 4.29 (m, 2 H) 4.49 - 4.63 (m. 1 H) 6.44 (d. J-Q.Q Hz1 1 H) 6.89 - 6.97 (m, 1 H) 6.98 - 7.05 (m, 1 H) 7.05 - 7.11 (m, 1 H) 7.27 (d, J*8.1 Hz, 2 H) 7.49 (d, J=8.1 Hz, 2 H).
A solution of (R)-tert-butyl 4-(4-ethoxy-1-(5'-fluoro-2'-methoxybiphenyl-4-yl)-4-oxobutan-2- ylamino)-4-oxobutanoate, (65 mg, 0.13 mmol) in 4M HCI in 1,4-dioxane (671 μL, 2.68 mmol) is stirred at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN), and then lyophilized to give (R)-4-(4-ethoxy-1-(5'-fiuoro-2'- methoxybiphenyl-4-yi)-4-oxobυtan-2-ylamino)-4~oxobutanoic acid (23 mg). HPLC retention time a 1,66 mtnutes (condition D); MS (m+1) = 432.3; 1H NMR (400 MHz1 DMSO-Cf6) δ ppm 1.17 (t, J=7.1 Hz, 3 H) 2.21 - 2.32 (m, 2 H) 2.32 - 2,40 (m, 2 H) 2.40 - 2.48 (m, 2 H) 2.77 (d, J=6.8 Hz, 2 H) 3.74 (s. 3 H) 4.03 (q, Λ«7.1 Hz, 2 H) 4.19 - 4.33 (m, 1 H) 7.04 - 7.20 (m, 3 H) 7.23 (d, Js8.1 Hz1 2 H) 7.43 (d, J*8.1 Hz, 2 H) 7.93 (d, J=8.3 Hz, 1 H)
Following compounds are prepared using simHar procedure as described in example 2-21;
Figure imgf000091_0001
Figure imgf000092_0001
Example 2-22: 1H NMR (400 MHz, CD3OD) δ ppm 1.23 (t, J-IA Hz, 3 H) 2.36 - 2.58 (m, 6 H) 2.85 (d, J=7.1 Hz1 2 H) 3.76 (β, 3 H) 4.10 (q, J=IA Hz1 2 H) 4.40 - 4.57 (m, 1 H) 7.01 (d, J=8.6 Hz, 1 H) 7.17 - 7.30 (m, 4 H) 7.39 (d, J-8.1 Hz, 2 H)
Example 2-23: 1H NMR (400 MHz1 DMSO-Qf6) δ ppm 1.16 (t, J=7.2 Hz, 1 H) 2.23 - 2.30 (m, 2 H) 2.34 - 2.40 (m, 2 H) 2.40 - 2.45 (m, 2 H) 2.75 (dd, J=6.6, 3.3 Hz, 2 H) 4.02 (q. J=7.2 Hz, 2 H) 4.19 - 4.30 (n% 1 H) 6.87 - 6.94 (m, 1 H) 6.93 - 7.02 (m, 1 H) 7.07 (dd, J-9.7. 3.2 Hz, 1 H) 7.22 (d, J-QA Hz, 2 H) 7.49 (d, J-SA Hz, 2 H) 7.94 (d, J=QA Hz, 1 H) 9.52 (S1 1 H) Example 2-24: 1H NMR (400 MHz1 DMSOd6) δ ppm 1.16 (t, J-7Λ Hz, 3 H) 2.22 - 2.32 (m, 2 H) 2.34 - 2.41 (m, 2 H) 2.43 (dd, J=β.8, 3.3 Hz, 2 H) 2.68 - 2.82 (m, 2 H) 4.02 (q, ./»7.1 Hz1 2 H) 4.17 - 4.35 (m, 1 H) 6.80 - 6.89 (m, 1 H) 6.93 (d, J*7.1 Hz1 1 H) 7.09 - 7.17 (m, 1 H) 7.17 - 7.29 (m, 3 H) 7.46 (d, J=8.3 Hz, 2 H) 7.93 (d, J=8.1 Hz1 1 H) 9.46 (br. s., 1 H)
Example 3-1: Syntheis of (R)»6-(1-(biphenyJ-4-yl)«4-ethoxy-4-oxobutan-2- ylcarbamoyl)pyrimidine-4-earboxyHc acid
Figure imgf000093_0001
To (/?)-ethyl~4-(biphenyl-4-yl)-3-(te/fΦυtoxycarbonylamino)butanoate (300 mg, 0.782 mmol) is added a solution of 4M HCI in 1,4-dioxane (3.92 ml, 15.65 mmol) at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to give (ft)-3-aminσ~4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride.
Next, to a suspension of pyrimidine«4,6-dicarboxytic acid (325 mg, 1.935 mmol), (R)-Z- amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride (250 mg, 0.774 mmol), WSC hydrochloride (148 mg, 0.774 mmol) and HOAt (105 mg, 0.774 mmol) in DMF (4 mL) and H2O (1 mL) is added DIPEA (0.135 mL, 0.774 mmol). After stirring for 14 hours, the reaction is quenched with H2O, and the products are extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN), and then lyophilized to give (R)-6-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2- ytearbamoyl)pyπmidine-4-carboxyi»c acid (84.8 mg). HPLC retention time = 1.32 minutes (condition B); MS (m+1) = 434.1 ; 1H NMR (400 MHz, DMSO-t/6) δ ppm 1.12 (t, J = 7.0 Hz1 3 H) 2.65 (A of ABX, Jab « 15.4 Hz, Jax = 5.8 Hz1 1 H) 2.73 (B of ABX, Jab ~ 15.4 Hz, Jbx * 7.9 Hz) 2.91 (A of ABX1 Jab - 13.6 Hz, Jax « 6.1 Hz, 1 H) 3.01 (B of ABX1 Jab ~ 13.6 Hz, Jbx s 8.2 Hz1 1 H) 4.01 (q, J - 7.0 Hz, 2 H) 4.59 - 4.68 (m, 1 H) 7.29 - 7.35 (m, 3 H) 7.41 - 7.45 (m, 2 H) 7.55 ~ 7.63 (m, 4 H) 8.32 (d, J = 1.35 Hz1 1 H) 9.19 (d. J = 9.1 Hz, 1 H) 9.50 (d, J = 1.35 Hz, 1 H) 14.11 (br s, 1 H). Following compounds are prepared using similar procedure as described in example 3-1 :
Figure imgf000094_0001
O
(J 1 f Ml "XL 1 55 mm.
Example 3-5 PyBOP instead 405 2
(R)-ethyl 4-<bιphenyl-4- (B)
Of WSCHCI1 y|)-3-<6-
HOAt hydroxynιcotinamido)bυt anoate
0°
H I JL 1 65 min.
Example 3-6 O 422 2 o
(R)-ethyf 4-(biphenyl-4-yl)-
3-(5-hydroxy-4-oχo-4H- pyraπ-2- carboκamιdo)butanoate
O p / O α
1 58 min
Example 3-7 N NR 405 .8
(R)-ethyl 3-(2- PyBOP instead (A) amιnopyrιmidme-5- of WSC HCI carboxamido)-4-(btphenyl- and HOAt
4-y!)butanoate
O
O
1 65 mm.
Example 3-8 404 .3
PyBOP instead (A)
(R)-ethyt 3-(6- of WSC.HCI amιnonιcotιnamιdo)-4- and HOAt
(biphenyl-4-yl)butartoate
Figure imgf000095_0001
Example 3-2: 1H NMR (400 MHz1 DMSO-d6) δ ppm 1.14 (t, J = 7.1 Hz1 3 H) 2.57 (d, J β 7.1 Hz, 2 H) 2.83 ~ 2.92 (m, 2 H) 4.03 (q. J = 7.1 Hz1 2 H) 4.43 - 4.52 (m, 1 H) 7.29 - 7.36 (m, 3 H) 7.42 - 7.46 (m, 2 H) 7.58 - 7.65 (m, 4 H) 8.30 (d. J » 8.4 Hz1 1 H) 8.64 (br S1 1 H).
Example 3-4: 1 H NMR (400 MHz1 DMSO-crø) δ ppm 1.13 (t, J « 7.1 Hz, 3 H) 2.55 (d, J » 6.9 Hz, 2 H) 2.82 - 2.92 (m, 2 H) 4.00 (q, J = 7.1 Hz, 2 H) 4.43 - 4.52 (m, 1 H) 7.29 - 7.35 (m, 3 H) 7.42 - 7.46 (m, 2 H) 7.58 - 7.65 (m, 4 H) 7.93 - 7.96 (m, 1H) 8.10 (d, J * 2.3 Hz, 1 H) 8.25 (d, J * 8.3 Hz1 1 H) 12.53 (d, J = 6.1 Hz1 1 H).
Example 3-5: 1H NMR (400 MHz1 DMSO-c/6) δ ppm 1.13 (t, J = 7.1 Hz, 3 H) 2.55 (d, J = 7.6 Hz, 2 H) 2.81- 2.92 (m, 2 H) 4.02 (q, J = 7.1 Hz. 2 H) 4.43 - 4.52 (m, 1 H) 7.29 - 7.36 (m, 3 H) 7.42 - 7.46 (m, 2 H) 7.57 - 7.65 (m, 4 H) 7.78 - 7.81 (m, 1H) 7.92 (d, J = 2.3 Hz, 1 H) 8.16 (d, J = 8.1 Hz1 1 H) 11.92 (s, 1 H).
Example 3-6: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (t, J = 7 Hz, 3 H) 2.55 - 2.67 (m, 2 H) 2.83- 2.94 (m. 2 H) 4.02 (q, J - 7 Hz1 2 H) 4.46 - 4.55 (m, 1 H) 6.82 (s. 1 H) 7.28 - 7.35 (m, 3 H) 7.42 - 7.46 (m ,2 H) 7.59 (d, J ~ 8.3 Hz1 2 H) 7.63 (d, J ~ 7.0 Hz, 2 H) 8.13 (s, 1 H) 8.89 (d, J - 8.6 Hz, 1 H) 9.56 (s, 1 H),
Example 3-7: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (t, J - 7 Hz, 3 H) 2.56 - 2.58 (m, 2 H) 2,83- 2.94 (m, 2 H) 4.02 (q, J « 7 Hz, 2 H) 4.46 - 4.55 (m, 1 H) 7.19 (s, 2 H) 7.30 - 7.35 (m. 3 H) 7.42 - 7.46 (m ,2 H) 7.58 - 7.65 (m, 4H) 8.22 (d. J * 8.1 Hz, 1 H) 8.60 (s, 1 H).
Example 3-9: Synthesis of (R)-benzyl 3-(4~butoxy-4-oxobutanamido)~4-(3'- chlorobiphenyt-4-yl)butanoate
Figure imgf000096_0001
A mixture of (R)-benzy! 3-amino-4-(3'-chlorobipbenyl-4-yi)butanoate hydrochloride (150 mg, 0.360 mmol), 4~bυtoxy-4-oxobutanoic acid (107 mg, 0.540 mtnol, 88% purity), EDCI (104 mg, 0.540 mmol), DIPEA {0.094 ml, 0.540 mmol) and HOAt (73.6 mg, 0.540 mmol) in DMF (2 mi) is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, and then the precipitated solid is collected on a funnel, washed with H2O, and dried under reduced pressure to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc ~ 100:0 to 0:100) to give (R)-benzyl 3-(4-butoxy-4- oxobutanamido)-4-(3<-chlorobiphenyl-4-yi)butanoate (178.9 mg): HPLC retention time - 1.47 minutes (condition B); MS (m+1) = 536.42; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90 - 0.94 (m, 3 H) 1.31 - 1.40 (m, 2 H) 1.56 - 1.63 (m, 2 H) 2.39 - 2.42 (m. 2 H) 2.48 ~ 2.62 (m, 4 H) 2.84 (A of ABX1 JΛ * 13.6 Hz, Jm * 8.1 Hz, 1 H) 2.97 (B of ABX1 JaB = 13,6 Hz, Jbx ~ 6.6 Hz, 1 H) 4.07 (t, J - 6.7 Hz, 2 H) 4.48 - 4.56 (m, 1 H) 5.12 (A of AB, J = 12.1 Hz, 1 H) 5.18 (B Of AB, J - 12.1 Hz, 1 H) 6.27 (br ά, J = 7.7 Hz, 1 H) 7.20 (d, J = 8.3 Hz1 1 H) 7.29 - 7.39 (m, 7 H) 7,42 - 7.47 (m, 3 H) 7.54 - 7.55 (m. 1 H).
Following compounds are prepared using similar procedure as described in example 3-8:
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Example 3-10: 1H NMR (400 MHz1 CHLOROFORM-d) δ ppm 1.29 (t. J - 7.2 Hz, 3 H) 1.58 - 1.64 (m, 4 H) 2.14 - 2.18 (m, 2 H) 2.28 - 2.32 (m, 2 H) 2.49 (A of ABX, Jab ~ 16.2 Hz, J3x = 5.3 Hz, 1 H) 2.53 (B of ABX1 Jab ~ 16.2 Hz, Jbx » 5.3 Hz, 1 H) 2.87 (A of ABX, Jab = 13.6 Hz, JaK = 8.1 Hz, 1 H) 2.99 (B of ABX, Jab = 13.6 Hz, Λ* * 6.8 Hz1 1 H) 3.65 (S1 3 H) 4.11 - 4.23 (m, 2 H) 4.48 - 4.56 (m, 1 H) 6.18 (br d, J = 8.8 Hz1 1 H) 7.26 - 7.37 (m, 4 H) 7,43 - 7.52 (m, 3 H) 7.56 (br t, J = 1.8 Hz, 1 H)
Example 3-11 : 1H NMR (400 MHz1 CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.40 - 2.51 (m, 4 H) 2.77 ~ 2.83 (m, 1 H) 2.91 - 2.97 (m, 3 H) 4.08 - 4.20 (m, 2 H) 4.46 - 4.54 (m, 1 H) 6.22 - 6.24 (m, 1 H) 7.18 - 7.23 (m, 3 H) 7.29 - 7.37 (m. 2 H) 7.43 - 7.49 (m, 3 H) 7.55 - 7.57 (m, 2 H) 8.44 (d, J = 4.8 Hz, 1 H) 8.48 (s, 1 H),
Example 3-12: 1H NMR (400 MHz. CHLOROFORM-d) δ ppm 129 (t, J - 7.1 Hz1 3 H) 1.53 - 2.20 (m, 9 H) 2.46 - 2.57 (m, 3 H) 2.86 (A of ABX1 Jβb * 13.6 Hz, J3x = 7.8 Hz, 1 H) 2.98 (B of ABX, Jab - 13.6 Hz, Jύκ ~ 6.6 Hz, 1 H) 3.65 (s, 3 H) 4.11 - 4.23 (m, 2 H) 4.47 - 4.55 (m. 1 H) 6.23 (br d, J = 8.6 Hz. 1 H) 7.24 - 7.26 (m, 2 H) 7.31 - 7.35 (m, 1 H) 7.41 - 7.45 (m, 2 H) 7.51 - 7.59 (m, 4 H).
Example 3-13: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J = 7.2 Hz, 3 H) 1.36 - 1.51 (m, 4 H) 1.84 - 1.94 (m, 2 H) 1.98 - 2.06 (m, 3 H) 2.24 - 2.32 (m, 1 H) 2.50 (A of ABX. Jab s 16.2 Hz, J3x - 5.3 Hz1 1 H) 2.53 (B of ABX, Jab = 16.2 Hz, J6x * 5.1 Hz, 1 H) 2.86 (A of ABX, J3J, = 13.6 Hz, Jax = 7.8 Hz, 1 H) 2.98 (B of ABX, J3b « 13.6 Hz1 Jbx = 6.6 Hz1 1 H) 3.66 (S1 3 H) 4.11 - 4.23 (m, 2 H) 4.46 - 4.55 (m, 1 H) 6.19 (br d, J = 8,8 Hz1 1 H) 7.24 - 7.26 (m, 2 H) 7.31 - 7.36 (m, 1 H) 7.41 - 7.45 (m, 2 H) 7.51 ~ 7,58 (m, 4 H). Exampie 3-14: 1H NMR (400 MHz1 CHLOROFORM-d) δ ppm 1.26 (t, J = 7.2 Hz, 3 H) 2.41 - 2.51 (m, 4 H) 2.62 ~ 2.66 (m, 2 H) 2.84 (A of ABX, Jab = 13.6 Hz. J9* - 7,6 Hz1 1 H) 2.92 (B of ABX. Jab = 13.6 Hz, J* ~ 6.6 Hz, 1 H) 3.06 - 3.10 (m, 2 H) 4.08 - 4.19 (m, 2 H) 4.46 - 4.55 (m, 1 H) 6.78 (d, J ~ 8.9 Hz, 1 H) 7.10 - 7.12 (m, 1 H) 7.16 (d, J - 7.8 Hz, 1 H) 7.20 - 7.22 (m, 2 H) 7.29 - 7.31 (m, 1 H) 7.35 (t, J - 7.7 Hz, 1 H) 7.42 - 7.47 (m, 3 H) 7.54 - 7.59 (m, 2 H) 8.48 (d, J - 1.0 Hz1 1 H).
Example 3-16: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1,24 (t, J ~ 7.1 Hz1 3 H) 2.38 - 2.42 (m. 2 H) 2.49 - 2.61 (m, 4 H) 2.82 - 3.00 (m, 2 H) 4.12 (q. J * 7.1 Hz1 2 H) 4.47 ~ 4.56 (m, 1 H) 5.12 (A of AB, J = 12.3 Hz, 1 H) 5.18 (B of AB, J - 12.3 Hz, 1 H) 6.26 (br d, J = 8.6 Hz, 1 H) 7.20 (d, J = 8.3 Hz, 2 H) 7.29 - 7.46 (m, 10 H) 7.54 - 7.54 (m, 1 H).
Example 3-17: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23 (t, J = 7.2 Hz, 3 H) 1.86 - 1.92 (m, 2 H) 2.14 - 2.18 (m, 2 H) 2.24 - 2.28 (m, 2 H) 2 50 - 2.63 (m, 2 H) 2.82 - 2.99 (m, 2 H) 4.11 (q, J = 7.2 Hz, 2 H) 4.53 - 4.54 (m, 1 H) 5.12 (A of AB1 J - 12.1 Hz, 1 H) 5.18 (B of AB1 J - 12.1 Hz, 1 H) 6.12 - 6.14 (m, 1 H) 7.19 - 7.54 (m, 13 H).
Example 3-18: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.2 Hz, 3 H) 1.67 (s, 9 H) 2.46 - 2 57 (m, 2 H) 2.74 - 2.96 (m. 4 H) 3.41 - 3.45 (m, 2 H) 4.09 - 4.17 (m, 2 H) 4.50 - 4.59 (m, 1 H) 6,95 (br d, J - 8.6 Hz1 1 H) 7.18 (d, J = 8.1 Hz1 2 H) 7.27 - 7.42 (m, 7 H) 7.51 (t, J - 1.8 Hz1 1 H) 7.61 - 7.65 (m, 1 H) 7.86 - 7.93 (m, 1 H).
Example 3-19: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J - 7.2 Hz1 3 H) 1.43 (S, 9 H) 2.37 - 2.40 (m, 2 H) 2.50 - 2.59 (m, 4 H) 2.98 (d, J - 7 3 Hz, 2 H) 4.13 - 4.21 (m, 2 H) 4.48 - 4.56 (m, 1 H) 6.35 (br d, J = 8.8 Hz. 1 H) 7.22 - 7.44 (m, 6 H) 7.54 - 7.54 (m, 1 H).
Example 3-20: Synthesis of (R)-ethyl 4-(3'-aminobiphenyl-4-yl)-3-(4-methoxy-4- oxobutanamido)butanoate
Figure imgf000102_0001
A suspension of (R)-ethyl 3~(4-methoxy-4-oxobutanamido)-4-(3'-nitrobiphenyl-4-yl)butanoate {123 mg, 0.278 mmol) and PάfC (59.2 mg, 0.028 mrnol) in EtOH (2 ml) is allowed to stir under hydrogen at room temperature for 5.5 hours. The reaction mixture is filtered, and the solution is concentrated to give (R)-ethyl 4-(3'-aminobiphenyi-4-yl)-3-(4-methoxy-4- oxot)utanamido)butanoate (105 mg); HPLC retention time ~ 0.84 minutes (condition B); MS (m+1) « 413.1; 1H NMR (400 MHz1 CHLOROFORM-c/) 6 ppm 1.28 (t, J e 7.2 Hz1 3 H) 2.41 ~ 2.65 (m, 6 H) 2.85 - 3.00 (m, 2 H) 3.67 (s, 3 H) 4.11 ~ 4.22 (m, 2 H) 4.46 - 4 54 (m, 1 H) 6.31 (br 6, J - 8.8 Hz, 1 H) 6.71 - 6.74 (m, 1 H) 6.95 - 7.02 (m ,2 H) 7.21 - 7.25 (m. 3 H) 7,48 - 7.50 (m, 2 H).
Following compounds are prepared using similar procedure as described in example 3-20
Figure imgf000102_0002
Example 3-22: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.03 - 2 11 (m. 2H) 2.48 - 2.62 (m, 4 H) 2.81 ~ 2.90 (m, 7 H) 2.95 - 3.00 (m, 1 H) 4.49 - 4.58 (m, 1 H) 5.07 - 5.18 (m, 2 H) 6.23 (br d, J = 8.6 Hz1 1 H) 6.79 - 6.82 (m, 1 H) 6.92 (s, 1 H) 7.15 - 7.20 (m, 3 H) 7.29 - 7.45 (m, 10 H) 7.52 - 7.53 (m, 1 H)
Example 3-23: Synthesis of (S)-benzyl 1-{2^{R)-1-(bipheny}«4-yl)-4-ethoxy-4-oxobutan- 2-ylamino)~2-oxoethyl)pyrrolidine-2-carboxylate trifluofoacetic acid salt
Figure imgf000103_0001
To a solution of (S)-benzyl 1-(2-tert-butoxy-2~oxoethyl)pyrrolidine-2-carboxylate (200 mg, 0.626 mmol) and triethylsilane (0.250 ml, 1.565 mmol) in DCM (3 ml). TFA (0.965 ml, 12.52 mmol) is added at room temperature. After stirring for 24 hours, the reaction is concentrated to give crude.
To a suspension of the crude, (ft)-ethyl 3-amino-4-(biphenyi-4-yl)butanoate hydrochloride (266 mg, 0.832 mmσi), WSCHCI (0.180 g, 0.939 mmoi) and HOAt (128 mg, 0.939 mmoi) in DMF (4 ml), DIPEA (0.328 ml, 1.878 mmol) is added. After stirring for 4 hours, the reaction is diluted with H2O and EtOAc. The products are extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude is subjected twice to column chromatography (heptane/EtOAc = 100:0 toO:100). Then, the obtained product is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1 % TFA) to 100% MeCN to give (S)-benzyi 1 -(2-((R)- 1 -(biphenyl-4-yl)-4-ethoxy~4-oxobutan-2-ylamino)-2-oxoethyl)pyrrolidine- 2-carboxylate tiifluoroacetic acid salt (28.5 mg) as a pale yellow solid; HPLC retention time « 1.84 minutes (condition D); MS (m+1) « 529.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 - 1.28 (m, 3 H) 1.74 - 1.85 (m, 2 H) 1.91 - 1.98 (m, 1 H) 2.09 - 2.19 (m, 1 H) 2.35 - 2.41 (m, 1 H) 2.46 (A of ABX, Jab - 15.7 Hz, Jax - 6.6 Hz, 1 H) 2.59 (B of ABX, Jab = 13.7 Hz, Jb)( = 5.7 Hz, 1 H) 2.78 - 2.83 (m, 1 H) 2.86 (A of ABX, Jab ~ 13.8 Hz, Jax = 8.1 Hz, 1 H) 2.99 (B of ABX, Jab = 13.7 Hz, Jto - 6.4 Hz. 1 H) 3.08 (A of AB, J ~ 16.5 Hz, 1 H) 3.35 (B of AB, J = 16.5 Hz, 1 H) 3.41 (dd, J = 9.1 and 5.1 Hz. 1 H) 4.11 - 4.20 (m, 2 H) 4.46 - 4.55 (m, 1 H) 5,10 (A of AB, J - 12.4 Hz, 1 H) 5.13 (B of AB1 J - 12.4 Hz, 1 H) 7.26 - 7.27 (m, 2 H) 7,31 - 7,38 (m, 6 H) 7.40 - 7.44 (m, 2 H) 7.49 - 7.56 (m, 4 H) 7.74 (br d, J - 8.6 Hz, 1 H). Example 3-24: Synthesis of (R)-ethyl 4-(3'-aeetamidobiphenyl-4-yl)-3-(4-methoxy-4- oxobutanamido)butanoate
Figure imgf000104_0001
A solution of (R)-ethy! 4-(3'-amιnobιphenyl-4-yl)-3~(4-methoxy-4-oxobutanarnιdo)butanoate (70 5 mg. 0.171 mmoi), Et3N (0 027 m), 0.205 mmoi) and Ac2O (0 019 ml, 0 206 mmol) m DCM {1.7 ml) is allowed to stir at room temperature for 65 hours. The reaction mixture is diluted with water. The products are extracted with DCM in a phase separator and concentrated to give crude (98 mg). The crude is purified by silica gel flash column chromatography (eluent DCM/MeOH ~ 10.1) to give (Ry-ethyl 4~(3'-acetamidobiphenyi-4-y!)- 3-{4-methoxy-4-oxobutanamido)butanoate (71.5 mg); HPLC retention time = 1.45 minutes (condition D); MS (m+1) = 455 4, 1M NMR (400 MHz, CD3CN, mixture of retainers, data for major rotamer) δ ppm 1.21 (t, J = 7.1 Hz, 3 H) 2 07 (s, 3 H) 2 31 - 2.34 (m, 2 H) 2.40 - 2.51 (m, 4 H) 2.82 - 2 84 (m, 2 H) 3 58 (s, 3 H) 4 07 (q, J ~ 7 1 Hz1 2 H) 4 34 - 4.43 (m, 1 H) 6.46 (br d, J = 8.9 Hz, 1 H) 7 28 - 7 39 (m, 4 H) 7 52 - 7 54 (m, 3 H) 7 80 (s, 1 H) 8 37 (br s, 1 H).
Example 3-25: Synthesis of (R)-3-(4-butoκy-4-oxobutanamido)-4-(3'-chlorobiphenyl-4- yl)butanoic acid
Figure imgf000104_0002
A suspension of (R)-benzyl 3-(4-butoxy-4-oxobutanamido)~4-(3'-chlorobiphenyl-4- yObutanoate (178.9 mg, 0 334 mmoi) and Pd/C (71 0 mg, 0 033 mmoi) in EtOAc (3 ml) is allowed to stir under hydrogen at room temperature for 1.5 hours. The reaction mixture is filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-3-(4- butoxy-4-oxobutanamido)-4-(3'~chlorobiphenyl-4-yi)butanoic acid (90.7 mg) as a white solid; HPLC retention time = 1.27 minutes (condition B); MS (m+1) « 446.24; 1H NMR (400 MHz1 CHLOROFORM-d) δ ppm 0.91 (t, J - 7.5 Hz1 3 H) 1.31 - 1.40 (m, 2 H) 1.55 - 1.62 (m , 2 H) 2.43 - 2.47 (m, 2 H) 2.52 - 2.69 (m , 4 H) 2.93 (A of ABX, JΛ ~ 13.7 Hz, Jax « 7.7 Hz, 1 H) 3.00 (B Of ABX, v/ab = 13.7 Hz, Λ* - 6.8 Hz, 1 H) 4.07 (t, J = 6.7 Hz1 2 H) 4.49 - 4.57 (m, 1 H) 6.31 (br d, J = 8.6 Hz, 1 H) 7.26 - 7.37 (m, 4 H) 7.43 - 7.46 (m, 1 H) 7.49 - 7.52 (m, 2 H) 7.55 (br t, J = 1.8 Hz, 1 H).
Chtral HPLC retention time - 4.33 min. Column: Daicel CHIRALPAK IA (4.6x100mm); flow rate « 1ml/min.; eluent: EtOH(containing 0.1% TFA)/heptane = 10/90 to 70/30 in 10min. (ϋnear gradient).
Following compounds are prepared using similar procedure as described in example 3-24:
Figure imgf000105_0001
Figure imgf000106_0001
Example 3-26: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23 (t, J ~ 7.1 Hz, 3 H) 1.86 - 1.93 (m, 2 H) 2.57 (A of ABX, Jab - 16.3 Hz, Jn ~ 5.7 Hz1 1 H) 2.64 (B of ABX1 J^ - 16.3 Hz, Jbx = 5.2 Hz, 1 H) 2.94 (A of ABX, J31, - 13,7 Hz1 J3x - 7.6 Hz, 1 H) 2.99 (B of ABX1 Jab = 13.7 Hz, Jbx - 7.2 Hz, 1 H) 4.10 (q, J = 7.1 Hz, 2 H) 4.51 - 4.60 (m, 1 H) 6.17 (br d, J = 8,6 Hz, 1 H) 7.26 - 7.37 (m, 4 H) 7.43 - 7.45 (m, 1 H) 7.49 - 7.52 (m, 2 H) 7,55 (br t, J - 1.8 Hz, 1 H),
Example 3-27: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.07 (quint, J * 7.4 Hz, 2 H) 2.51 - 2.63 (m, 4 H) 2.82 - 3.02 (m, 8 H) 4,50 - 4.59 (m, 1 H) 6.28 (d, J ~ 8.6 Hz, 1 H) 6.78 - 6.81 (m, 1 H) 6.91 (d, J - 1.8 Hz, 1 H) 7.26 - 7.36 (m, 6 H) 7.41 - 7.44 (m, 1 H) 7.47 - 7.50 (m, 2 H) 7.53 - 7.54 (m, 1 H).
Example 3-28: 1H NMR (400 MHz1 CHLOROFORM-d) δ ppm 1.24 (t, J - 7.2 Hz, 3 H) 2.44 - 2.69 (m , 6 H) 2.93 (A of ABX, J*, - 13.7 Hz, Jaκ ~ 7.8 Hz, 1 H) 3.00 (B of ABX, Jat> ~ 13.7 Hz, Jbx = 6.7 Hz, 1 H) 4.12 (q, J = 7.2 Hz1 2 H) 4.49 - 4.57 (m, 1 H) 6.35 (br ά, J ~ 8.6 Hz, 1 H) 7,26 - 7.37 (m, 4 H) 7.43 - 7.46 (m, 1 H) 7.49 - 7,52 (m, 2 H) 7.55 (br t, J ~ 1.6 Hz. 1 H). Example 3*29: Synthesis of (R)~3«(4~{benzyloxy)-4-oxobutan-smido}-4«(3'~ chlorobiphenyi-4-yl)butanoic acid
Figure imgf000107_0001
A solution of succinic acid mono-benzyl ester (71.1 mg, 0.342 mrnol), EDCI (65.5 mg, 0.342 mmol) and HOAt (46.5 mg, 0.342 mmol) in DMF (1 mi), which is allowed to stir at room temperature for 1 hour, is added to a solution of (R)-3~amino-4-(3'-chlorobiphenyl-4- yl)bυtar»oic acid (66 mg. 0.228 mmol) and DIPEA (0.080 ml, 0.456 mmol) in a mixed solvent DMF (2 ml) and water (2 ml). The reaction mixture is allowed to stir for 3 hours, and then diluted with H2O. The products are extracted twice with EtOAc. The combined organic layer is washed with brine, dried over Na2SO^ filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-3-(4-(benzyloxy)-4-oxobutanamido)-4-(3'-chlorobiphenyl-4- yl)butanoic acid (42.4 mg) as a white solid; HPLC retention time = 1.22 minutes (condition B); MS (m+1) = 480.35; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.44 - 2.75 (m, 6 H) 2.86 - 2.99 (m, 2 H) 4.48 - 4.56 (m, 1 H) 5.11 (s, 2 H) 6.29 (br d, J - 8.6 Hz1 1 H) 6.97 - 7.07 (m, 10 H) 7.25 - 7.36 (m, 2 H) 7.42 - 7.50 (m, 2 H) 7.54 (br t, J ~ 1.6 Hz, 1 H).
Example 3-30: Synthesis of 4-(bipheny}-4-yl)-3-(1- (carboxymethy!)cyclopentanecarboxamido)butanoic acid
Figure imgf000107_0002
To tert-butyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (110 mg, 0.287 mmol), a solution of 4 M HCI in 1,4-dioxane (0.668 ml, 2.67 mmol) is added. After stirring for 1 h, the reaction mixture is concentrated to give crude 3-amino-4-biphenyl~4-yl-butyric acid tert-butyl ester hydrochloride. Next, to a solution of EOCI (51.2 mg, 0,267 mmoI),1-hydroxy-7-azabenzσtriazote (36.4 mg, 0.267 mmol) and 6 :1 mixture of 1-(2-{benzyloxy)-2-oxoethyl)cyclopentanecarboxyiic acid and 2-(1-(benzyloxycarbonyl)cyciopentyl)acetic acid (65.6 mg, 0.214 mmol) in DMF (1 ml), which is stirred for 1.5 hours in advance, the crude 3-amino-4-biphenyl-4-yt-butyric add tert- butyl ester hydrochloride and DIPEA (0.093 ml, 0.535 mmol) are added. After stirring for 2.5 hours, the reaction mixture is diluted with H2O, and the products are extracted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc ~ 100:0 to 0:100) to give crude tert-butyl 3-(1-(2~{benzyloxy)-2- oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-4-yt)butanoate (38 mg).
Next, to the solution of the crude tert-butyl 3-(1-(2-(benzyloxy)-2- oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-4-yl)butanoate (38 mg) in DCM (0.7 ml), TFA (0.263 ml, 3.42 mmol) is added. After stirring for 1 hour, the reaction mixture is concentrated to give crude 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-4- (biphenyl-4-yl)butanoic acid (39 mg).
Next, A suspension of the crude (39 mg) and Pd/C (16.6 mg, 7.8 μmol) in EtOH (1 ml) is allowed to stir under hydrogen at room temperature for 4 hours. The reaction mixture is filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give 4-(biphenyl- 4-yl)-3-(1-(carboxymethyl)cyclopentanecarboxamido)butanoic acid (12.7 mg); HPLC retention time = 1.16 minutes (condition B); MS (m+1) = 410.1; 1H NMR (400 MHz, DMSO- d6) δ ppm 1.39 - 1.53 (m, 6 H) 1.83 - 1.98 (mτ 2 H) 2.34 - 2.45 (m, 2 H) 2.53 (s, 2 H) 2.73 - 2.86 (m, 2 H) 4.21 - 4.33 (m, 1 H) 7.27 (d, J = 8.1 Hz. 2 H) 7.32 - 7.37 (m, 2 H) 7.43 - 7.46 (m, 2 H) 7.55 - 7.58 (m, 2 H) 7.62 - 7.64 (m, 2 H) 7.84 (br d, J = 8.9 Hz, 1 H),
Example 3-31: Synthesis of (R)-ethyf 4-(3'-chIorobiphenyi«4-yl)-3«(2-oxo>2,3- dihydrooκazole-5-carboxamido)butanoate Ct
Figure imgf000109_0001
To a solution of (R)-ethyl 4-(3'-chlorobiphenyl-4-yl)-3-(2-methoxyoxazole-5- carboxamido)butanoate, intermediate 14, (103 mg, 0.23 mmol) in dioxane (3 rr>L) is added 4 N solution of HCI in dioxane (0.29 rnL, 1.16 mmol). The crude was stirred at room temperature for 2 hrs. The crude is concentrated and is diluted in water and EtOAc. The oganic layer is washed with brine, dried over MgSO4, filtered, and concentrated, 50% of the crude is purified via RP-HPLC (SunFire C 18, H2O(0.1%TFA)/CH3CN) to give (R)-ethyl 4~{3'- chlorobiphenyM-yl)-3-(2-oxσ~2,3-dihydrooxazole-5-carboxamido)butaπoate (38 mg) as a white solid. HPLC retention time - 1.66 minutes (condition A); MS (m+1) ~ 429.4; 1H NMR (400 MHz, CHLOROFORM-cO δ ppm 1.29 (t, J-7.1 Hz, 3 H) 2.51 - 2.69 (m, 2 H) 2.95 (dd, 1 H) 3.05 (dd, 1 H) 4.19 (q, 2 H) 4.58 - 4.75 (m, 1 H) 6.83 (d, J-8.8 Hz, 1 H) 7.26 - 7.33 (m, 4 H) 7.35 (t, J-7.7 Hz, 1 H) 7.45 (dt, J=7.6, 1.5 Hz, 1 H) 7.51 (d, J=8.3 Hz, 2 H) 7.56 (t, J=1.8 Hz, 1 H) 8,45 (br. s., 1 H).
Example 3-32: Synthesis of (R)-ethyl 4-(3'-chlorobiphenyl-4-yl)-3-(2-oxo-2,3- dihydroth»azole-5-carboxamido)butanoate
^o
Figure imgf000109_0002
To a solution of (R)-ethyl 4-(3'-chlorobiphenyl-4-yl)-3-(2-methoxythiazole-5- carboxamido)butanoate, intermediate 13, (170 mg, 0.37 mmol) in dioxane (5 mL) is added a solution of 4 M HCI in dioxane (0.5 mL, 2.00 mmol). The crude is stirred at room temperature for 3 hrs. The crude is concentrated. Part of the crude is purified via RP-HPLC {SυnFire C18, H2O(0.1%TFA)/CH3CN) to give (95 mg) of (R)-ethyl 4-(3'-chlorobiphenyi-4-y!)- 3-(2-oxo-2,3-dihydrothiazole-5-carboxamido)butanoate as a white solid. HPLC retention time = 1.82 minutes (condition D); MS (m+1) = 445.2. 1H NMR (400 MHz1 CHLOROFORM- cf) δ ppm 1.29 (t, J=7.1 Hz1 3 H) 2.46 - 2.70 (m, 2 H) 2.78-2-97 (m, 1 H) 3.07 (dd, J=13.0, 6.2 Hz, 1 H) 4.11 - 4.28 (m, 2 H) 4.51 - 4.69 (m, 1 H) 6.64 (d, J~8.1 Hz, 1 H), 7.19-7.42 (m, 5 H) 7.44 (d, Jfeβ.1 Hz1 1 H) 7.48-7.62 (m, 3H), 9.54 (br. s., 1 H).
Example 3-33: Synthesis of (R)-ethyl 4-(3'-chlorobiphenyl-4-yl)-3-(5-oxo-4,5-dJhydro- 1,3,4«oxadla2ole-2-carboxamido)butanoate
y^
Figure imgf000110_0001
To a solution of (R)-ethyl 4-(3'-chlorobiphenyl~4-yl)-3-(2-hydrazinyl-2- oxoacetamido)butanoate$ intermediate 12, (289 mg, 0.72 mmol) in THF (8.5 mL) is added CDI (139 mg, 0.86 mmol) at room temperature. After stirring for 18 hour at room temperature, the reaction is quenched with H2O and 1 M HCI, and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)ZCH3CN) and then lyophilized to give (R)-ethyl 4-(3(- chlorobiphenyl^-yiJ-S-Cδ-oxo^^-dihydro-I .S^-oxadiazole^-carboxamidoJbutanoate (100 rng). HPLC retention time ~ 1.67 minutes (condition A); MS (m+1) « 430.2; 1H NMR (400 MHz, DMSO-Of6) δ ppm 1.14 (t, J~7.1 Hz1 3 H) 2.52 - 2.70 (m. 2 H) 2.84 (do, J=13.7, 8.4 Hz, 1 H) 2.90 (dd, J=13.7, 8.4 Hz, 1 H) 4.02 (q, >7.1 Hz, 2 H) 4.42 - 4.58 (m, 1 H) 7.30 (d, J=8.1 Hz. 2 H) 7.37 - 7.43 (m, 1 H) 7.47 (t, J=7.B Hz, 1 H) 7.57 - 7.66 (m, 3 H) 7.70 (t, ^1.9 Hz, 1 H) 8.98 (d, J=8.8 Hz, 1 H) 12.94 (s, 1 H).
Example 3-34: Synthesis of (R)-3-(3-Carboxymethyl-ureido)-4-(3'-chloro-biphenyi-4-yl)- butyric acid ethyl ester
Figure imgf000111_0001
To a solution of t-butyt 2-aminoacetate (19.08 mg, 0.145 mmof) and DIEA (18.8 mg, 0.145 mmol) in DMF (1 mL) is added Intermediate 45 (50 mg, 0.145 mmol) and the mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure to give (R)-3-(3-tert-butoxycarbonyimethyl-ureido)-4-(3'-chtoro-biphenyl-4-yl)-butyric acid ethyl ester.
Next, to a solution of the above diester (70 mg, 0.147 mmol) in methylene chloride (2 mL) is added TFA (4 mL) and the mixture is stirred at room temperature for 18 hours. The solvents are removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 35% MeCN/water to 100% MeCN (+0.1% TFA). Lyophilization of the proper fractions gives the title compound; HPLC Retention time 1.42 minutes (condition C); MS 419.1 (M+1); 1H NMR (400 MHz1 DMSO-dβ): δ ppm 1.17 (t, J=7.07 Hz, 3H), 2.41 (d, J-7.07 Hz, 2H), 2.77-2.79 (m, 2H), 3.66-3.68 (m, 2H)1 4.04 (q, J=7.07 Hz, 2H)1 4.08-4.15 (m, 1H), 6.13 (t, J=5.81 Hz, 1H), 6.24 (d, J=8.59 Hz, 1H)1 7.28-7.30 (m, 2H), 7.39-7,42 (m, 1H)1 7.48 (t, J = 7.83 Hz, 1H)1 7.62-7.64 (m, 3H)1 7.71 (t, J=1.77 Hz, 1H), 12.42 (s, 1H).
Example 4-1: Synthesis of (R)-4-biphenyi-4-yl-3-{2-1H-tetrazol-5-yl-acetylamino)- butyric acid ethyl ester
Figure imgf000111_0002
H intermediate 2
To a solution of (R)-4-biphenyl-4-yi-3-tert-butoxycarbonylamino-butyric acid ethyl ester (100 mg, 0.261 mmol) in DCM (3 mL) at room temperature is added TFA (1 mL, 12,98 mmol) and the mixture is stirred at room temperature for 0.5 hour. The mixture is concentrated under reduced pressure to give (R)-3-amino-4-biphenyl-4-yl-bυtyric acid ethyl ester trifluoroacetic salt. HPLC retention time = 1.50 minutes (condition C); MS (m+1) = 384. Next, to a suspension of (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester trifiuoroacetic salt (0.074 g, 0.261 mmol) in DCM (10 mL) at room temperature is added 1H~tetrazole-5- acetic acid (0.050 g, 0.392 mmol). To the mixture at ice bath temperature is added bis(2- oxo-3-oxazolidinyl)phosphinic chloride (0.100 g, 0.392 mmol) and quickly followed by DlPEA (0.137 ml, 0.783 mmol). The reaction mixture is slowly warmed up to room temperature and stirred overnight. The reaction is extracted with DCM. The combined organic layer is washed with saturated NaHCO3, saturated NHΛCI, brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-4-biphenyl-4-yl-3-(2- 1H-tetrazol~5-yl-acetylamino)-butyric acid ethyl ester. HPLC retention time ~ 1.04 minutes (condition E); MS (m+1) = 394.
Example 4-2: Synthesis of (R)-ethyl 4~(biphenyl-4-yi}*3-{6- (methylsulfonamido)nicotinamido)butanoate
Figure imgf000112_0001
To a solution of (R)-ethyl 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride (103 mg, 0.32 mmol) and 6-(methylsu!fonamido)nicotinic acid, intermediate 15, (84 mg, 0.39 mmol) in CH^CI2 (2 mL) and DMF (2 mL) is added TEA (0.18 mL, 1.29 mmol) and HATU (159 mg, 0.42 mmol) at room temperature. The crude is stirred at room temperature for 2 hrs. The crude is quenched with saturated NaHCO3, diluted in EtOAc. The organic layer is washed with six times with water, brine, dried over MgSOΛ, filtered, and concentrated. The crude is purified via RP-HPLC (SunFire C18, H2O(0.1%TFA)/CH3CN) to give (R)-ethyl 4- (biphenyl-4-yl)-3-(6-(methylsυlfonamido)nicotinamido)butanoate as a white solid (4.1 mg). HPLC retention time - 1.61 minutes (condition A); MS (m+1) « 482.3. 1H NMR (400 MHz, CHLOROFORM-^) δ ppm 1.22 (t, J-7.2 Hz, 3 H), 2.56 (t, J=4,8 Hz, 2 H), 2,84 - 2.92 (m, 1 H), 3.05 (dd, J-13.6, 6.1 Hz, 1 H). 3.16 (s, 3 H), 4.08 - 4.18 (m, 2 H)1 4.57 - 4.71 (m, 1 H), 7.03 (d, >8.3 Hz. 1 H), 7.10 (d, J-8.3 Hz, 1 H), 7.22 (d, J«8.3 Hz, 2 H), 7.26 - 7,31 (m. 1 H), 7.33 - 7.40 (m, 2 H), 7.44 - 7.54 (m, 5 H), 7.98 (dd. J=8.8, 2.3 Hz, 1 H), 8.52 (s, 1 H). Following compounds are prepared using similar procedure as described in example 4-2.
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Example 4-3: 1H NMR (400 MHz, DMSO-αfe) δ ppm 1.13 (t, J=7.1 Hz, 3 H) 2.52 - 2.67 (m, 2 H) 2.88 (dd, J=13.3, 8.0 Hz, 1 H) 2.95 (dd, >13.3, 8.0 Hz1 1 H) 3.05 (s, 3 H) 4.02 <q, J-7.1 Hz, 2 H) 4.46 - 4.65 (m, 1 H) 7.23 (d, J=8.8 Hz, 2 H) 7.34 (d, _/*8.1 Hz, 2 H) 7.36 - 7.42 (m, 1 H) 7.46 (t, J-7.8 Hz1 1 H) 7.59 - 7.66 (m, 3 H) 7.69 (t, J=1.8 Hz1 1 H) 7.75 (d, J=8.6 Hz, 2 H) 8.31 (d, J-8.3 Hz, 1 H) 10.07 (s, 1 H)
Example 4-4: 1H NMR (400 MHz, DMSO-^6) δ ppm 1.13 (t, J-7Λ Hz, 3 H) 1.28 (t, J«7.5 Hz, 3 H) 2.59 (d, J=7.1 Hz, 2 H) 2.81 - 2.94 (m, 2 H) 2.97 (q, J-7,6 Hz, 2 H) 4,03 (q, J=7.1 Hz1 2 H) 4.40 - 4.55 (m, 1 H) 7.32 (d, J-8.1 Hz1 2 H) 7.36 - 7.42 (m, 1 H) 7.46 (t, J=7.8 Hz, 1 H) 7.58 - 7.65 (m, 3 H) 7.69 (t> J=1.9 Hz1 1 H) 8.18 (s, 1 H) 8.52 (d, J=8.3 Hz, 1 H)
Example 4-5: 1H NMR (400 MHz1 CD3OD) δ ppm 1.24 (t, J=7.1 Hz, 3 H) 2.38 - 2.60 (m, 6 H) 2.78 - 2.94 (m, 2 H) 4.10 (q, J=7.1 Hz. 2 H) 4.42 - 4.55 (m, 1 H) 7.32 (d, J«8.3 Hz, 2 H) 7.40 (t. J=7.83 Hz, 1 H) 7.50 - 7.53 (m, 4 H) 7.60 (t, J-1.89 Hz, 1 H)
Example 4-6: 1H NMR (400 MHz, DMSO-Cf6) δ ppm 1.13 (t, J-7,2 Hz, 3 H) 1.25 (t, J=7.6 Hz, 3 H) 2.53 - 2.65 (m, 2 H) 2.80 (q. J-7.6 Hz, 2 H) 2.84 - 2.96 (m, 2 H) 4.02 (q, J=7.1 Hz, 2 H) 4.42 • 4.60 (m, 1 H) 7,31 (d, J=8,3 Hz1 2 H) 7.37 - 7.42 (m, 1 H) 7.47 (t. J=7.8 Hz, 1 H) 7.59 (S, 1 H) 7,60 - 7.65 (m, 3 H) 7.69 (t, J=1.9 Hz1 1 H) 8.48 (d, J=*8.6 Hz1 1 H)
Example 4-7: 1H NMR (400 MHz, DMSO-c/β) δ ppm 1.13 (t, J=7.1 Hz1 3 H) 2.52 - 2.65 (m, 2 H) 2.85 (dd, >13.6, 5.8 Hz, 1 H) 2.91 (dd, J=13.6, 5.8 Hz1 1 H) 4.02 (q, J=7.1 Hz, 2 H) 4.38 - 4.60 (m, 1 H) 5.89 (s, 1 H) 7.31 (d, J-8.3 Hz, 2 H) 7.37 - 7.42 (m, 1 H) 7.46 (t, J=7.8 Hz, 1 H) 7.58 - 7.65 (m. 3 H) 7.69 (t. J-I. B Hz, 1 H) 8.10 (d, J=B.Q Hz1 1 H)
Example 4-8: 1H NMR (400 MHz, CD3OO) δ ppm 1.22 (t, J=7.2 Hz, 3 H) 2.56 - 2.72 (m. 2 H) 2.95 (d, J-7.3 Hz, 2 H) 4.11 (q, J=7.2 Hz, 2 H) 4.53 - 4.73 (m, 1 H) 7,28 - 7.36 (m, 3 H) 7.39 (t, J=7.8 Hz1 1 H) 7.48 - 7.55 (m. 3 H) 7.58 (t, J«1.8 Hz, 1 H)
Example 4-9: 1H NMR (400 MHz1 DMSO-cfe) δ ppm 1.13 (t, J=7.1 Hz, 3 H) 2.53 - 2.71 (m, 2 H) 2.85 (dd, J=13.7, 8.3 Hz1 1 H) 2.96 (dd. J=13,7, 8.3 Hz1 1 H) 4.02 (q, J-7.1 Hz, 2 H) 4.45
- 4.63 (m, 1 H) 6.93 (dd, J-9.9. 2.3 Hz1 1 H) 7.30 (d, >β.1 Hz1 2 H) 7.36 - 7.42 (m, 1 H) 7.47 (t, J-7.B Hz, 1 H) 7.61 (d, J=8.3 Hz1 3 H) 7.69 (t, J*1.β Hz, 1 H) 7.75 (d, J=9.9 Hz, 1 H) 8.45 (d, ./=9.1 Hz, 1 H) 13.41 (d, J=2.Q Hz, 1 H)
Example 4-10: 1H NMR (400 MHz, OMSOd6) δ ppm 1.13 (t, J=IA Hz1 3 H) 2.60 (d, J=7.6 Hz, 2 H) 2.90 (d, J=*6.8 Hz1 2 H) 4.02 (q, J-12 Hz, 2 H) 4.39 - 4.53 (m, 1 H) 7.11 (s, 1 H) 7.32 (d, J=BA Hz, 2 H) 7.37 - 7.43 (m, 1 H) 7.47 (t. J=7.8 Hz, 1 H) 7.60 - 7.66 (m, 3 H) 7.70 (t, J=1.9 Hz, 1 H) 8.72 (d, J=8.3 Hz, 1 H) 11.76 (br. s.. 1 H)
Example 4-11: 1H NMR (400 MHz, CHLOROFORM-cf) δ ppm 1.27 (t, J=7.1 Hz, 3 H) 2.47 - 2.69 (m, 2 H) 2.90 (dd, J=13.6, 7.8 Hz1 1 H) 3.06 (dd, J=13.6, 6.6 Hz1 1 H) 3.06 (broad s, 1H) 4.07 - 4.28 (m, 2 H) 4.52 - 4.74 (m, 1 H) 7.21 - 7.37 (m, 5 H) 7.38 - 7.44 (m, 1 H) 7.48 (d, J-BA Hz, 2 H) 7.53 (t, J=1.δ Hz1 1 H) 9 50 (br. s., 1 H).
Example 4-12; 1 H NMR (400 MHz, DMSO-Of6) δ ppm 1.13 (t, J=IA Hz, 3 H) 2.59 (d, J=7.3 Hz, 2 H) 2.76 - 3.03 (m, 2 H) 4.03 (q, J-7.1 Hz1 2 H) 4.39 - 4.66 (m, 1 H) 7.02 (d, 1 H) 7-28 - 7.54 (m, 4 H) 7.54 - 7.80 (m, 4 H) 8.05 (dd, J=8.6, 2.3 Hz. 1 H) 8.45 (d, J=8.3 Hz, 1 H) 8.61 (br. s., 1 H).
Example 4-13: Synthesis of (R)-ethyl 4-(5'-fluoro-2'-methoxybipheny}-4-yI)«3-{oxazole~ 5«carboxamido)butanoate
Figure imgf000118_0001
To a solution of oxazole-5-carboxyiic acid (70 mg, 0.61 mmol) in DMF (1.5 mL) and DCM (1.5 mL) is added (R)-ethyl 3-amino«4~(5'-fluoro-2'-methoxybiphenyl-4-yi)butanoate hydrochloride, intermediate 10, (150 mg, 0.41 mmol), HATU (233 mg. 0.61 mmol), and TEA (284 μL, 2.04 mmol). After stirring for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP- HPLC (SυnFire C18, H8O(0.1% TFA)ZCH3CN), and then lyophilized to give (R)-ethyl 4-(5'- ftuoro-2'-methoxybiphenyl-4-y[)-3-(oxazole-5-carboxamido)butanoate (157 mg). HPLC retention time = 1.50 minutes (condition A); MS (rn-M) = 427.4: 1 H NMR (400 MHz, CHLOROFORM-cO δ ppm 1.19 (t, J-7.2 Hz1 3 H) 2.46 - 2.62 (m, 2 H) 2.86 (dd, ,/=13.6, 8.1 Hz, 1 H) 3.02 (dd, J=13.6, 6.1 Hz, 1 H) 3.67 (s, 3 H) 4.05 - 4.15 (m, 2 H) 4.52 - 4.69 (m, 1 H) 6,76 - 6.82 (m, 1 H) 6.83 - 6.96 (m, 2 H) 7.1 1 - 7.21 (m, 3 H) 7.37 (d, J=8.1 Hz, 2 H) 7.61 (S1 1 H) 7.80 (s, 1 H)
Following compounds are prepared using similar procedure as described in example 4-13:
Figure imgf000118_0002
Example 4-14: 1H NMR (400 MHz, CD3OD) δ ppm 1.21 (t, J=7.1 Hz, 3 H) 2.61 - 2.68 (m, 2 H) 2.95 (d, J-7.1 Hz, 2 H) 3.74 (s, 3 H) 4.10 (q, >7.1 Hz, 2 H) 4.60 - 4.73 (m. 1 H) 6.43 (s, 1 H) 6.98 - 7.06 (m, 3 H) 7.27 (d, >8.1 Hz, 2 H) 7.38 - 7.48 (m, 2 H) 8.78 (d, J=8.8 Hz, 1 H)
Example 4-15: Synthesis of 5-[(R)-1-(3''Chloro-biphenyl-4-ylmethyl)-2~ethoxycarbonyl- ethylcarbamoyO-1 H-pyrazole-3-carboxyUc acid
Figure imgf000119_0001
To a mixture of Intermediate 17-1 (130 mg, 0.367 mmol), 1H-pyrazole-3,5-dicarboxylic acid (74.5 mg, 0.477 mmol), EDCI (91 mg, 0.477 mmol) and HOBt (64.5 mg, 0.477 mmof) in DMF (3 ml) is added triethylamine (149 mg, 0.203 mmol) and the mixture is stirred at room temperature for 18 hours. Any insoluble material is removed by filtration and the filtrate is chromatographed by HPLC using a gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA). Lyophitization of the proper fractions gives the title compound; HPLC Retention time 1.31 minutes (condition C); MS 456.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7,07 Hz1 3H), 2.54-2.67 (m, 2H)1 2.84-2.97 (m, 2H), 4.02 (q. J=7.07 Hz, 2H), 4.54 (m, 1H)1 7.11 (s, broad, 1H), 7.32 (d, J=8.08 Hzt 2H), 7.39 (m, 1H), 7.46 (t, 1 H)1 7.62 (d, J=8.08 Hz, 3H)1 7.69 (s. 1H), 8.41 (s, broad, 1H).
The following compounds are prepared using the procedure described for Example 4-15.
Figure imgf000119_0002
Figure imgf000120_0002
Example 4-16: 1H NMR (400 MHz, DMSO-d6); δ ppm 1.11 (t, J=7.07 Hz, 3H)1 2.59-2.79 (m, 2H), 2.87-2.92 (m, 1H), 2.98-3.04 (m, 1H), 4.01 (q, J=7.33 Hz, 2H), 4.57-4.66 (m, 1H)1 7.30- 7.32 (m, 2H), 7,37-7.40 (m,1H), 7.45 (t, J=7.58 Hz, 1H)1 7.59-7.61 (m, 3H), 7.68 (t, J=1.77 Hz, 1H), 8.16 (S, 1H), 9.10 (d, J=9.35 Hz, 1H), 9.31 (s, 1H).
Example 4-17: (R)-4*(3'-Chtoro-b(phenyt-4«yl}-3^(3-hydroxy<'isoxazole-5-carbonyl)* aminol-butyric acid ethyl ester
Figure imgf000120_0001
To a solution of intermediate 16-1 (40.6 mg, 0.315 mmol) and HATU (144 mg, 0.378 mmol) in DMF (2 mL) is added pyridine (74.7 mg( 0.76 mL, 0.944 mmol) and the mixture is stirred at room temperature for 15 minutes. Then Intermediate 17-1 is added and stirring is continued for 2 hours. Any insoluble is removed by filtration and the filtrate is chromatographed by HPLC using a gradient of 10% MeCN/water to 100% MeCN (+0.1 % TFA). LyophHization of the proper fractions gives the title compound. HPtC Retention time 1.36 minutes (condition C): MS 429.1 (M+ 1); 1H NMR (400 MHz1 DMSO-d6) δ ppm 1.13 (t, J=7.07 Hz, 3 H) 2.60 (dd, J=6.95, 3.66 Hz, 2 H) 2.81 - 2.95 (m. 2 H) 4.02 (q, J=7.24 Hz, 2 H) 4.49 (d, J=7.83 Hz, 1 H) 6.49 (s, 1 H) 7.31 (d, J=8.34 Hz, 2 H) 7.37 - 7.43 (m, 1 H) 7.47 (t, J«7.83 Hz, 1 H) 7.59 - 7.66 (m, 3 H) 7.70 (t, J*1.89 Hz, 1 H) 8.83 (d, J-8.84 Hz, 1 H).
The following compounds are prepared using the procedure described for Example 4-17
Figure imgf000120_0003
Figure imgf000121_0001
Example 4-18: 1H NMR (400 MHz, DMSO-d€) δ ppm 1.12 (t, J=7.07 Hz1 3 H) 2.60 (dd, J=6.95, 2.65 Hz, 2 H) 2.82 - 2.96 (m, 2 H) 4.02 (q, J=7,07 Hz. 2 H) 4.45 - 4,58 (m, 1 H) 7.31 <d, J=8.34 Hz, 2 H) 7.37 - 7.42 (m, 1 H) 7.47 (t, J=7.83 Hz, 1 H) 7.58 - 7.65 (m, 3 H) 7.69 (t, J=M .77 Hz, 1 H) 7.72 (s, 1 H) 8.55 (s, 1 H) 8.63 (d, J=8.59 Hz, 1 H).
Example 4-19: 1H NMR (400 MHz1 DMSO-d6) δ ppm 1.13 (t, J=7.07 Hz, 3 H) 2.54 - 2.75 (m, 2 H) 2.76 - 3.02 (m, 2 H) 4.02 (q, J=7.07 Hz1 2 H) 4.29 - 4.70 (m, 1 H) 6.49 (s, 1 H) 6.96 - 7.23 (m, 1 H) 7,30 (d, J=8.08 Hz, 2 H) 7.44 - 7.58 (m, 3 H) 7.64 (d, J=*8.08 Hz, 2 H) 8.83 (d, J=8.59 Hz. 1 H) 11.68 (s. 1 H).
Example 4-20: (R)-3-t(5-Carboxymethyf-furan'2-carbonyl)-aminoJ-4-(31>chloro-biphenyl- 4-yl)-butyric acid ethyl ester and Example 4-21 : (R)-3«[(5-Carboxymethy!-f uran-2-carbonyJ)-aminoI-4-(3'-chJoro-biphenyl- 4-yi)~butyric acid
Figure imgf000122_0001
The reaction is performed similar to Example 4-15 using Intermediate 16-1 and Intermediate 44 to give {R)-4-(3'-chloro-biphenyl-4-yl)-3-[(5-methoxycarbonylmethyl-furaιv2-carboπyl)- amino]~butyric acid ethyl ester. HPLC Retention time 1.38 minutes (condition C). Next, to a solution of the above diester (235 mg, 0.486 mmol) in EtOH (5 mL) is added 1N NaoH (0.486 mL) and the mixture is stirred at room temperature for 4 hours. The solvent is removed under reduced pressure and water (4 mL) is added. The solution is acidified with 1N HCI and the mixture is extracted with EtOAc. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA). Lyophilization of the proper fractions gives the title compounds. (R)-3-[(5-Carboxymethyj- furan-2-carbonyl)-amino]-4-{3'-chloro-biphenyl-4-yl)-butyric acid ethyl ester. HPLC Retention time 1.35 minutes (condition C); MS 470.0 (M+1); 1H NMR (400 MHz1 DMSO-d6) δ ppm 1.13 (t, Je 7.07 Hz, 3H), 2.50-2.64 (m, 2H), 2.81-2.95 (m, 2H), 3.74 (s, 2H), 4.01 (q, J=7.07 Hz1 2H), 4.51 (m, 1H), 6.99 (d, J=3.28 Hz, 1H)1 7.31 (d, J«8.34 Hz1 2H), 7.38-7.41 (m, 1 H), 7.47 (t, 1H), 7.62 (d, J-8.08 Hz, 3H), 7.69 (t, 1H), 8.24 (d, J=8.84 Hz, 1H). (R)-3-[(5-Carboxymethyl-furan-2-carbonyl)-amino]~4-(3'-chloro-biphenyl-4-yl)-butyric acid. HPLC Retention time 0.94 minutes (condition C); MS 442.0 (M+1); 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.44-2.58 (m, 2H), 2.81-2.94 (m, 2H), 3.74 (S, 2H), 4.48 (m, 1H), 6.39 (d, J-3.28 Hz, 1H),6.99 (d. J-3.54 Hz, 1H), 7.30 (d, J=8.34 Hz, 2H), 7.38-7.41 (m, 1H), 7.47 (t, 1H), 7.62 (d, J=8.34 Hz, 3H). 7.70 (t, J=1.77 Hz11H). 8.22 (d, J=8.84 Hz1 1 H).
Example 4-22: (RJ^S'-Chloro-biphenyM-ylJ-S-KaH-tetrazole-δ-carbonyO-amJno]' butyric acid ethyl ester
Figure imgf000123_0001
To a solution of intermediate 16-1 in DCM (8 mi) at room temperature is added 2-(4- methoxy-benzyl)-2H-tetrazoie~5-carbonyl chloride and followed by TEA (0.293 ml, 2.100 mmol). The reaction is stirred at room temperature for 5 min. The reaction is quenched by brine and is extracted with DCM. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (15% to 40% EtOAc/Heptane). The obtained residue in TFA (5 ml, 64,9 mmol) is heated at 80 °C for 0.5 hours. The reaction is concentrated under reduced pressure to give (R)~4-(3'-chloro«biphenyl-4-yl)-3-((2H-tetrazc4e- 5-carbonyf)-amino]-butyric acid ethyl ester.
HPLC retention time ~ 1.31 minutes (condition B); MS (m+1) = 414.1; 1H NMR (400 MHz, DMSO-dδ) δ ppm 1.11 (t, J«7.1 Hz. 3 H), 2.63 (dd, J=15.4, 5.6 Hz, 1 H), 272 (dd, J=15.4, 8.3 Hz, 1 H), 2.86 - 2.99 (m, 2 H), 4.02 (q, J=7.1 Hz, 2 H), 4.55 - 4.67 (m, 1 H)1 7.32 (d, J=8.1 Hz, 2 H), 7.37 - 7.42 (m, 1 H), 7.46 (t, J=7.8 Hz1 1 H), 7.60 (d, J-8.1 Hz1 3 H), 7.68 (t, J-1.8 Hz, 1 H), 9.37 (d, J«8.8 Hz1 1 H).
Following compounds are prepared using similar procedure as described in example 4-22;
Figure imgf000123_0002
Figure imgf000124_0002
Example 4-23. 1H NMR (400 MHz, DMSOd6) δ ppm 1.12 (t J=7.2 Hz1 3 H), 2.59 - 2.67 (m, J*15.4( 5.6 Hz, 1 H)1 2.72 (dd, J=15.4, 8 3 Hz, 1 H)1 2.85 - 3.01 (m, 2 H), 4.02 <q, J«7.1 Hz, 2 H)1 4.55 - 4.67 (m, 1 H), 7.11 - 7.19 (m, 1 H), 7.32 (d, J«8.3 Hz, 2 H), 7.42 - 7.51 (m, 3 H), 7.61 (d. J-8.3 Hz, 2 H), 9.34 (d, J==8.8 Hz, 1 H).
Example 4-24: 1H NMR (400 MHz, DMSOd6) δ ppm 1.95 - 2.06 (m. 2 H), 2.75 - 2.92 (m, 6 H)1 2.95 (dd, J-13.5, 5.9 Hz, 1 H), 3.06 (dd, J-13.6, 8.1 Hz, 1 H), 4.64 - 4.76 (m, 1 H), 6.78 <dd, J=8.1 , 2.3 Hz. 1 H), 6.88 (d, J=1.5 Hz, 1 H), 7.17 <d. J=8.1 Hz, 1 H), 7.34 - 7.41 (m, 3 H)1 7.46 (t, J=7.8 Hz, 1 H), 7.59 - 7.65 (m, 3 H), 7.70 (t, J«1.8 Hz1 1 H), 8.43 (d, J=8.8 Hz, 1 H),
Example 4-25: 2-{(R)«1 -Biphenyl-4-ylmethyl~2-ethoxycarbQnyl-«thylamino)-oxazole-4- carboxylic acid ethyl ester
Figure imgf000124_0001
To a suspension of (R)~4-biphenyl-4-yl-3-ureido-butyric acid ethyl ester (169 mg, 0.518 mmol) in EtOH (5 ml) at ice bath is added ethyl bromopyruvate (0.098 ml, 0.777 mmol). The reaction is warmed up slowly to room temperature and stirred at reflux overnight. The reaction is concentrated and the residue is taken up in EtOAc and H2O. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-((R)-1~biphenyl-4-ylmethyl-2-ethoxycarbonyl- ethylamino)-oxazole-4-carboxy)ic acid ethyl ester. HPLC retention time = 1.42 minutes (condition B); MS (m+1) = 423,
Example 4-26: Synthesis of (ff,£)-ethyJ 4-(4-(benzyloxy)-1~(3'-chlorobiphenyl-4-yl)-4- oxobutan-2-ylamino)-4-oxobut-2-enoate
CL Cl
Figure imgf000125_0001
To (R)~her\zy\ 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate (87.6 mg, 0.183 mmol) is added a solution of HCI in 1 ,4-dioxane (0.456 mL, 1.825 mmol) at room temperature. After stirring for 3 hours, the reaction mixture is concentrated under reduced pressure to give (R)-benzyl 3- amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride. A mixture of (R)-benzyl 3-amino-4- (3'-chlorobipheny!-4-yl)butanoate hydrochloride, fumaric acid monoethyl ester (33.4 mg, 0.220 mmol), EDCI (63.3 mg, 0.330 mmol), DIPEA (0.058 ml, 0.330 mmol) and HOAt (44.9 mg, 0.330 mmol) in DMF (1.8 ml) is allowed to stir at room temperature for 3 hour. The reaction mixture is diluted with water, and then the products are extracted wtih EtOAc. The organic layer is washed with NH4OH, 1M HCIaq and brine, dried over Na2SO4, filtered, and concentrated to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc = 100:0 to 0:100) to give (R£)-ethyl 4-(4-(benzyloxy)-1-(3'- chlorobiphenyl-4-yl)-4-oxobutan-2-yiamino)-4-oxobυt-2-enoate (72.9 mg); HPLC retention time = 1.40 minutes (condition B); MS (m+1) = 506.3; 1 H NMR (400 MHz. CHLOROFORM- d) δ ppm 1.31 (t, J = 7.1 Hz, 3 H) 2.58 (A of ABX, JΛ ~ 16.4 Hz, J8x - 5.3 Hz, 1 H) 2.6 (B of ABX1 Jab = 16.4 Hz, Jbx = 5.1 Hz1 1 H) 2.88 (A of ABX, J36 = 13.6 Hz, J8x = 8.1 Hz, 1 H) 3.03 (B of ABX, Λb = 13.6 Hz, JM ~ 6.3 Hz, 1 H) 4.24 (q, J ~ 7.1 Hz, 2 H) 4.56 - 4.64 (m, 1 H) 5.12 (A Of AB, J = 12.1 Hz, 1 H) 5.18 (B of AB, J = 12.1 Hz, 1 H) 6.57 (br d, J = 9.1 Hz, 1 H) 6.77 (A Of AB, J = 15.4 Hz. 1 H) 6.81 (B of AB, J = 15.4 Hz, 1 H) 7.19 (br d, J - 8.1 Hz, 2 H) 7.29 - 7.47 (m, 10 H) 7.53 ~ 7.54 (m, 1 H).
Example 4-27: Synthesis of (R)-ethyl 4-(3'«chlorobiphenyl-4-yl)-3-(2- (ethoxycarbonylamino)acetamido)butanoate
Figure imgf000126_0001
A mixture of (R)-ethyl 3-amino-4-(3'-ch(orobiphenyl-4-yf)butanoate hydrochloride (173 mg, 0.488 mmol), 2-(ethoxycarbonylamino)acetic acid (86 mg, 0.488 mmol), EDCI (140 mg, 0.732 mmol), DIPEA (0.128 ml, 0.732 mmol) and HOAt (100 mg, 0.732 mmol) in DMF (2.5 ml) is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, and then the precipitated solid is collected on a funnel, washed with H2O, and dried under reduced pressure to give crude. The obtained residue is purified by silica gei flash column chromatography (heptane/EtOAc = 100:0 to 0:100) to give (R)~ethyl 4-(3'~ chlorobiphenyl-4-yi)-3-(2-(ethoxycarbonylamino)acetamido)butanoate (161 mg); HPLC retention time = 1.16 minutes (condition B); MS (m+1) = 447.3; 1H NMR (400 MHz1 CHLOROFORM-d) δ ppm 1.25 (t, J = 7.07 Hz, 3 H) 1.29 (t, J = 7.07 Hz1 3 H) 2.50 (A of ABX, Jab = 16.2 Hz, JM - 5.3 Hz, 1 H) 2.54 (B of ABX1 J^ * 16.2 Hz, J^ « 5.3 Hz, 1 H) 2.89 (A of ABX, Jab = 13.6 Hz, J8x ~ 7.8 Hz, 1 H) 2.99 (B of ABX1 JβB * 13.6 Hz1 Jbx = 6.6 Hz, 1 H) 3.80 (be d, J ~ 5.8 Hz, 2 H) 4.12 - 4.23 (m , 4 H) 4.48 - 4.56 (m, 1 H) 5.15 (br s, 1 H) 6.64 (br d. J « 8.8 Hz, 1 H) 7.25 - 7 .27 (m, 2 H) 7.29 - 7.38 (m, 2 H) 7.43 - 7.46 (m, 1 H) 7.49 - 7.52 (m, 2 H) 7.55 - 7.56 (m, 1 H).
Following compounds are prepared using similar procedure as described in example 4-27:
Figure imgf000126_0002
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Exampfe 4-29: 1H NMR {400 MHz, CHLOROFORM-d) δ ppm 131 (t, J ~ 72 Hz, 3 H) 264 (A of ABX, J85 » 16.8 Hz, Jm~ 51 HZ, 1 H) 268 (8 of ABX, Jab =168 Hz, Jbκ = 51 Hz, 1 H) 297 (A OfABX, J46 = 137 Hz, Jn = 81 HZ, 1 H) 308 (B of ABX, J86 «137 Hz, Jbx~Q7 Hz1 1 H)425(q, J=72Hz, 2 H) 4.58-4.67 (m( 1 H) 666 (d, J = 8.8 Hz 1 H) 680 (A of AB, J = 15.4 Hz11 H) 697 (B of AB, J = 154 Hz, 1 H) 727-737 (m, 4 H) 7.43-745 (m, 1 H) 751 (d, J « 83 Hz, 2 H) 7.55 - 756 (m, 1 H) Example 4-30: 1H NMR (400 MHz, CD3OD) δ ppm 1.21 <t, J=7.2 Hz1 3 H) 1 34 (t, J-7.6 Hz1 3 H) 2.68 (d, J=6.8 Hz, 2 H) 2.84 - 2.87 (m, 2 H) 2.98 - 3.00 (m, 2 H) 4.10 (q, J=7.1 Hz, 2 H) 4.66 - 4.78 (m, 1 H) 7.27 - 7.37 (m, 6 H) 7.41 - 7.47 (m, 1 H) 7,54 (s, 1 H).
Example 4-31 : 1H NMR (400 MHz, CD3OD) δ ppm 1.20 (t, J=7.1 Hz, 3 H) 2.28 (s, 3 H) 2.62 (d, J=7.1 Hz, 2 H) 2.93 (dd, J=13.6, 6.8 Hz, 1 H) 3.00 (dd, J=13.6, 7.3 Hz, 1 H) 4.09 (q, J-7.1 Hz1 2 H) 4.60 - 4.76 (m, 1 H) 6.45 (s, 1 H) 7.24 - 7,40 (m, 4 H) 7.42 - 7.51 (m, 3 H) 7.54 (t, J«1.8 Hz, 1 H).
Example 4-32: 1H NMR (400 MHz, CD3OD) δ ppm 1.20 (t, J=7.2 Hz1 3 H) 2.58 - 2.66 (m, 2 H) 2.68 (s. 3 H) 2.94 (dd, J=14.2, 7.8 Hz, 1 H) 2.99 (dd, J-13.6, 6.8 Hz, 1 H) 4.09 (q, >7.2 Hz. 2 H) 4.58 - 4.76 (m, 1 H) 7.27 - 7.31 (m, 1 H) 7.33 (d, J-8.3 Hz, 2 H) 7.37 (t. J-7.8 Hz, 1 H) 7.46 - 7.49 (m, 1 H) 7.51 (d, J-8.1 Hz, 2 H) 7.55 (t, J«1.9 Hz1 1 H) 8.06 (s, 1 H) 8.49 (d, J=8.6 Hz, 1 H).
Example 4-33: 1H NMR (400 MHz, CD3OD) δ ppm 1.21 (t, J*7.1 Hz, 3 H) 2.60 - 2.70 (m, 2 H) 2.72 (s. 3 H) 2.97 (dd, J=13.6, 8.1 Hz, 1 H) 3.03 (dd, J«13.9, 6.6 Hz, 1 H) 4.11 (q, J=7.2 Hz, 2 H) 4.67 - 4.81 (m, 1 H) 7.27 - 7.33 (m, 1 H) 7.33 - 7.41 (m, 3 H) 7.48 - 7.52 (m, 1 H) 7.54 (d, J=8.3 Hz, 2 H) 7.57 (t, J=1.8 Hz, 1 H) 8.70 (d, J=8.3 Hz1 1 H) 8.92 (s, 2 H),
Example 4-34: 1H NMR (400 MHz, CD3OO) δ ppm 1.21 (t, J-7.2 Hz, 3 H) 2.43 (β, 3 H) 2.63 (d, J=6.6 Hz, 2 H) 2.94 (dd, J-13.9, 7.1 Hz, 1 H) 2.99 (dd, J=13.6, 7.6 Hz, 1 H) 4.10 (q, J=7.1 Hz, 2 H) 4.62 - 4.74 (m, 1 H) 7.26 - 7.30 (m, 1 H) 7.30 - 7.39 (m. 3 H) 7.43 - 7.51 (m, 3 H) 7.53 (t, J«1.8 Hz, 1 H) 8.15 (s, 1 H).
Example 4-35: 1H NMR (400 MHz, CD3OD) δ ppm 1,20 (t, J*7.1 Hz, 3 H) 2.64 (dd, J=15.4, 7.3 Hz1 1 H) 2.70 (dd, J=15.9, 6.3 Hz, 1 H) 2.99 (d, J=7.3 Hz1 2 H) 4.10 (q, J-7.2 Hz, 2 H) 4.65 - 4.79 (m, 1 H) 7.14 (dd, J=10.2, 8.7 Hz, 1 H) 7.30 (ddd, J*8.8, 4.1 , 2.8 Hz, 1 H) 7.32 - 7.37 (m, 2 H) 7.37 - 7.46 (m, 3 H) 7.67 (s, 1 H) 8.28 (s, 1 H) 8.62 (d, J=8.6 Hz, 1 H).
Example 4-36: 1H NMR (400 MHz, CD3OD) δ ppm 1.20 (t, J=7.2 Hz, 3 H) 1.33 (t, J-7.7 Hz, 3 H) 2.66 (d. J=6.8 Hz, 2 H) 2.83 (q, J-7,6 Hz1 2 H) 2 98 (d, J=7.1 Hz. 2 H) 4.10 <q, J=7.1 Hz, 2 H) 4.65 - 4.79 (m, 1 H) 7.14 (dd, J-10.2, 8.7 Hz, 1 H) 7.30 (ddd, J=8.8, 4.1, 2.8 Hz, 1 H) 7.32 - 7.37 (m, 2 H) 7.37 - 7.46 (m. 3 H) 7.54 (s, 1 H) 8.49 (d, J=8.8 Hz, 1 H). Example 4-37: 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.33 (t, J-7Λ Hz1 3 H) 2.22 (s, 3 H) 2.57 - 272 (m. 2 H) 2.99 (dd, J=13.6, 8.1 Hz, 1 H) 3.16 (dd, J-13.6, 6.3 Hz, 1 H) 4.15 - 4.33 (m, 2 H) 4.60 - 4.82 (m, 1 H) 5.55 (s. 1 H) 6.10 (s, 1 H) 7.15 (d( J=8.8 Hz1 1 H) 7.34 (d, J*8,1 Hz1 3 H) 7.39 (t. J*7.7 Hz1 1 H) 7.48 (dt, J-7.6, 1.5 Hz, 1 H) 7.54 (d. >8.1 Hz, 2 H) 7.58 (t, JSS1.8 Hz, 1 H) 7.72 (s, 1 H).
Example 5-1 : Synthesis of (R)-4-{biphenyl-4-yl)-3-{3-carboxypropanamido)butanoic acid
Figure imgf000132_0001
To a solution of (R)-4-(1-(biphβnyl-4-yl)~4-ethoxy-4-oxobυtan-2~yiamino)-4-oxobυtanoic acid (61.2 mg, 0.160 mmol) in THF (1.6 mL) and methanol {0.2 mL), aqueous 1M NaOH solution (0.638 mL, 0.638 mmol) is added at room temperature. After stirring for 45 minutes, the reaction is quenched with aqueous 0.1 M HCI and is extracted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (f?)-4-(btphenyl-4-yl)-3-(3-carboxypropanamido)butanoic acid (54.9 mg). HPLC retention time = 1.33 minutes (condition A); MS (m+1) ~ 356.1; 1H NMR (400 MHz1 CD3OD) δ ppm 2.40-2.56 (m, 6 H) 2.83 - 2,94 (m, 2 H) 4.43 - 4.50 (m, 1 H) 7.20-7.32 (m, 3 H) 7.41 (t, 2 H1 J = 7.7 Hz) 7.53-7,60 (m, 4H).
Following compounds are prepared using similar procedure as described in example 5-1 :
Figure imgf000132_0002
H0A^-1vNΛ^γ0H Aq.
H 0
NaOH, 1.10 mtn.
Example 5-2 (R)-3-(3-carboxy- 389.9
THF, propionylamino)-4- s T (A)
MeOH, rt
(4'-chloro-biphenyl- Example 2-2
4-yI)-butyric a cid
0' Aq.
0
O i O 0 NaOH, 0.87 min.
Example 5-3 (R)-3-(3-carboxy- 373.9
H % THF, (A) propionylamino)-4-
Example 2-1 MeOH, rt
(4'-fluoro-biphenyl-
4-yl)-butyric a cid
F h Aq.
NaOH, 0.69 min.
Example 5-4 H 0 374.0
(R)-3-(3-carboxy~ THF, (8)
R I MeOH, propioπylamino)-4- rt Example 2-3
(3'-flυoro-biphenyi-
4-yl)-bυtyric acid
CJ Aq.
NaOH1 0.80 min.
Example 5-5 373.9
H 0 THF1 (B)
H ό
{R)-3-(3-carboxy- MeOH, rt Example 2-4 propionylamiπo)-4-
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Example 5-2: 1H NMR (400 MHz1 CD3OD) δ ppm 2,38-2.42 (m, 2 H) 2.45 - 2.54 (m, 4 H) 2.82- 2.94 (m, 2 H) 4.42 - 4.48 (m, 1 H) 7.12 - 7,16 (m, 2 H) 7.31 (d, J-8.4 Hz, 2 H) 7.41 (d, J = 8.6 Hz1 2 H) 7.54 (d, J = 8.1 Hz, 2 H) 7.58 (d, J = 8.6 Hz.2 H).
Example 5-3: 1H NMR (400 MHz, CD3OD) δ ppm 2.39-2.42 (m, 2 H) 2.45 - 2.54 (m, 4 H) 2.85 (A of ABX, Jab ~ 13.6 Hz1 Jax = 7.6 HZ, 1 H) 2.91 (B of ABX, Jab - 13.6 Hz, Jbx - 6.2 HZ, 1 H) 4.42 - 4.48 (m, 1 H) 7.12 - 7.16 (m ,2 H) 7.31 (A of AB1 J = 8.2 Hz, 2 H) 7.52 (B of AB, J = 8.2 Hz, 2 H) 7.58 - 7.62 (m, 2 H)
Example 5-4: 1H NMR (400 MHz, CD3OD) δ ppm 2.39-2.44 (m, 2 H) 2.46 - 2.55 (m, 4 H) 2.86 (A of ABX, Jab = 13.6 Hz, Jax ~ 7.6 HZ, 1 H) 2.92 (B of ABX, Jab = 13.6 Hz, Jbx = 6.3 HZ, 1 H) 4.42 - 4.49 (m, 1 H) 7.01 - 7.06 ((D 1I H) 7.32 (br d, J = 8.1 Hz1 2 H) 7.39 - 7.45 (m, 2 H) 7.55 (d, J - 8.1 Hz1 2 H)
Example 5-5: 1H NMR (400 MHz, CD3OD) δ ppm 2.40-2.43 (m, 2 H) 2.46 - 2.56 (m, 4 H) 2.87 (A Of ABX1 Jab = 13.5 Hz, Jax = 7.7 HZ1 1 H) 2.93 (B of ABX1 Jab = 13,5 Hz, Jbx = 6.2 HZ, 1 H) 4.43 - 4.50 (m, 1 H) 7.13 - 7.18 (m, 1 H) 7.20 - 7.24 (m, 1 H) 7.31- 7.35 (m ,3 H) 7.44 - 7.48 (m, 3 H) 7.99 (br d, J = 8.3 Hz, 1 H)
Example 5-6; 1H NMR (400 MHz, CD3OD) δ ppm 2.39-2.43 (m, 2 H) 2.45 - 2,57 (m, 4 H) 2.87 (A Of ABX1 Jab « 13,6 Hz, Jax » 7.6 HZ, 1 H) 2.94 (B of ABX, Jab = 13.6 Hz, Jbx - 6.1 HZ, 1 H) 4.44 - 4,51 (m, 1 H) 7.28 - 7.35 (m, 7 H) 7.46 (br d, J - 7.9 Hz, 1 H)
Example 5-7: 1H NMR (400 MHz, CD3OD) δ ppm 2.40-2.52 (m, 6 H) 2.83 - 2.92 (m, 2 H) 3.77 (s, 3 H) 4.44 - 4.47 (m, 1 H) 6.96 - 7.05 (m, 2 H) 7.23 - 7.30 (m, 4 H) 7.39 -7.41 (m, 2 H)
Example 5-8: 1H NMR (400 MHz, CD300) δ ppm 2.21 (s, 3 H) 2.41-2.55 (m, 6 H) 2.82 - 2.94 (m, 2 H) 3.77 (s, 3 H) 4.45 - 4.48 (m, 1 H) 7.15 - 7.28 (m, 8 H)
Example 5-9: 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.56 (dd, J*5.81, 15.92Hz, 1H)1 2.66 (dd, J=7.07, 15.92Hz, 1H), 2.90 (dd. J=6.06, 13.64Hz, 1H), 3.00 (dd, J=8.08, 13.64Hz, 1H), 4.53-4.64 (m, 1 H), 7.30 (d, J=8.34Hz, 2H), 7.33 (t, J=7.58, 1 H), 7,56 (d, J=8.34Hz, 2H), 7.62 (d, J=7.07Hz. 2H)1 7.95 (dd, J=1.26, 5,05Hz, 1H). 9,01-9.07 (m, 2H), 9.33 (d, J=1.52Hz, 1H), 12.28 (s, 1H).
Example 5-10: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 - 2.49 (m, 2 H), 2.75 - 2.86 (m, 2 H), 3.83 (s, 2 H), 4.19 - 4.31 (m, 1 H), 7.26 (d, J=8.3 Hz, 2 H), 7.31 - 7.38 (m, 1 H), 7.45 (t, J=7.6 Hz, 2 H), 7.56 (d, J=8.3 Hz, 2 H), 7.61 - 7.67 (m, 2 H), 8.40 (d, J«8.1 Hz, 1 H), 12.26 (br. s., 1 H), 16.02 (br. s., 1 H).
Example 5-11 : 1H NMR (400 MHz, DMSO-d6) δ ppm 2,46 - 2.59 (m, 2 H), 2.86 - 2.88 (m, 2 H), 4.41 - 4.49 (m, 1 H), 7.29 - 7.36 (m, 3 H), 7.42 ~ 7.46 (m. 2 H), 7.58 - 7.65 (m, 4 H), 8.26 (d, J=8 Hz, 1 H), 8.64 (br s, 2 H) 12.24 (br. s.. 1 H). Example 5-12: 1H NMR (400 MHz, DMSO-dδ) δ ppm 2.54 - 2.70 (m, 2 H), 2.88 - 3.03 (m, 2 H)1 4.56 - 4.65 (m, 1 H), 7.29 - 7.34(m, 3 H). 7.41 - 7.45 (m, 2 H), 7.55 - 7.63 (m, 4 H), 8.33 (s, 1 H), 9.15 (d, J « 9.1 Hz, 1 H)1 9.49 (s. 1 H)1 12,30 (br s, 1 H), 14.11 <br s, 1 H).
Example 5-13: 1 H NMR (400 MHz1 CD3OD) 6 ppm 2.38 - 2.57 (m. 6 H) 2.87 (A of ABX1 Jab
- 13.6 Hz, Jax = 7.6 Hz1 1 H) 2.95 (B of ABX1 Jab = 13.6 Hz, Jbx - 6.1 Hz1 1 H) 4.44 - 4.51 (m. 1 H) 7.06 - 7.14 (m, 2 H) 7.31 - 7.37 (m, 5 H) 7.48 (dd, J ~ 8 8 and 5.1 Hz1 1 H).
Example 5-14: 1H NMR (400 MHz1 CD3OD) δ ppm 2.39 (s, 3 H) 2.39 - 2.55 (m, 6 H) 2.85 (A of ABX, Jab = 13.5 Hz, Jax = 7.5 HZ, 1 H) 2.90 (B of ABX, Jab - 13.5 Hz, Jbx = 6.4 Hz, 1 H) 4.42 - 4.49 (m. 1 H) 7.13 (br d, J ~ 7.3 Hz, 1 H) 7.26 - 7.30 (m, 3 H) 7.36 - 7.40 (m, 2 H) 7.52 (d. J - 8.3 Hz1 2 H).
Example 5-15: 1H NMR (400 MHz, CD3OO) δ ppm 2.38 - 2.55 (m, 6 H) 2.86 (A of ABX, Jab « 13.6 Hz, Jax « 7.8 HZ, 1 H) 2.93 (B of ABX1 Jab = 13.6 Hz, Jbx * β.1 HZ, 1 H) 4.42 - 4.49 (m. 1 H) 6.86 - 6.92 (m, 1 H) 7.19 - 7.25 (m, 2 H) 7.33 - 7.35 (m, 2 H) 7.55 - 7.58 (m, 2 H).
Example 5-16: 1 H NMR (400 MHz, CD3OD) δ ppm 1.27 (t, J = 7.6 Hz. 3 H) 2.39 - 2 55 (m, 6 H) 2.70 (q, J = 7.6 Hz, 2 H) 2.85 (A of ABX, Jab = 13.6 Hz, Jax * 7.5 HZ, 1 H) 2.90 (B of ABX1 Jab = 13.6 Hz, Jbx « 6.4 HZ1 1 H) 4.42 - 4.49 (m, 1 H) 7.16 (br d, J= 7.6 Hz, 1 H) 7.28
- 7.33 (m, 3 H) 7.38 - 7.42 (m, 2 H) 7.52 - 7.54 (m, 2 H).
Example 5-17: 1H NMR (400 MHz1 DMSO-dδ) δ ppm 2.47 - 2.50 (m, 2 H) 2.82 - 2.91 (m, 2 H) 4.40 - 4.49 (m, 1 H) 7.29 (d, J = 8.3 Hz, 2 H) 7.31 - 7,36 (m, 1 H) 7.42 - 7.46 (m, 2 H) 7.59 (d, J ~ BA Hz. 2 H) 7.63 - 7.65 (m, 2 H) 7.95 (br d, J = 2.3 Hz1 1 H) 8.11 (br d, J - 2.3 Hz. 1 H) 8.25 - 8.27 (m, 1 H) 12.24 (br s, 1 H) 12.48 (br s, 1 H).
Example 5-18: 1H NMR (400 MHz, CD3OD) δ ppm 2.38 - 2.55 <m, 6 H) 2.86 (A of ABX1 Jab = 13.6 Hz, Jax « 7.8 Hz, 1 H) 2.92 (B of ABX, Jab = 13.6 Hz, Jbx - 6.3 Hz, 1 H) 4.43 - 4.50 (m, 1 H) 7.26 (br d, J = 7.3 Hz, 1 H) 7.35 (d, J « 8.1 Hz1 2 H) 7.51 - 7.58 (m, 4 H) 7.64 (br d, J « 7,8 Hz, 1 H).
Exampte 5-19: 1H NMR (400 MHz, CD3OD) δ ppm 2.39 - 2.42 (m, 2 H) 2.45 - 2,56 (m, 4 H) 2.88 (A of ABX. Jab - 13 6 Hz, Jax = 7.6 Hz, 1 H) 2.95 (B of ABX, Jab « 13.6 Hz. Jbx = 6.2 Hz, 1 H) 4.44 - 4.51 (m, 1 H) Θ.86 - 6.89 (m, 1 H) 7.38 - 7.41 (m, 2 H) 7.63 - 7.70 (m, 3 H) 8.02 - 8.04 (m, 1 H) 8.18 - 8.21 (m, 1 H) 8.45 (br t, J = 1.9 Hz, 1 H),
Example 5-20: 1H NMR (400 MHz1 CD3OD) δ ppm 2.39 - 2.56 (m, 6 H) 2.87 (A of ABX, Jab = 13.6 Hz, Jax - 7.6 Hz, 1 H) 2.93 (B of ABX, Jab = 13.6 Hz. Jbx = 6.3 Hz, 1 H) 4.43 - 4.50 (m, 1 H) 7.36 <d, J - 8.3 Hz1 2 H) 7,58 - 7.62 (m, 4 H) 7.85 - 7.87 (m, 2 H),
Example 5-21 : 1H NMR (400 MHz, CD300) δ ppm 2.39 - 2.54 (m, 6 H) 2.85 (A of ABX, Jab = 13.6 Hz, Jax - 7.5 Hz, 1 H) 2.91 (B of ABX, Jab « 13.6 Hz, Jbx ~ 6.3 HZ, 1 H) 3.84 (s, 3 H) 4.42 - 4.49 (m, 1 H) 6,86 - 6.89 (m, 1 H) 7.11 - 7.17 (m, 2 H) 7.29 - 7.34 (m, 3 H) 7.52 - 7,54 (m, 2 H).
Example 5-22: 1H NMR (400 MHz, DMSOd6) δ ppm 2.43 - 2.46 (m, 2 H), 2.81 - 2,91 (m, 2 H) 4.40 - 4.49 (m, 1 H) 6.33 (d, J ~ 9.6 Hz1 1 H) 7 28 - 7.35 (m, 3 H) 7.42 - 7.46 (m, 2 H) 7.58 (d. J = 8.1 Hz, 2 H) 7,63 - 7.65 (m, 2 H) 7.81 (dd, J * 9.6, 2,8 Hz, 1 H) 7.93 (br s, 1 H) 8.14 (d, J = 8.3 Hz, 1 H) 11,92 (br s, 1 H) 12.19 (br s, 1 H).
Example 5-23: 1H NMR (400 MHz. CD3O0) δ ppm 2.39 - 2.42 (m, 2 H) 2,44 - 2.55 (m. 4 H) 2.86 (A of ABX, Jab = 13.6 Hz, Jax = 7.6 Hz, 1 H) 2.93 (B of ABX, Jab = 13.6 Hz, Jbx = 6.3 HZ, 1 H) 4.43 - 4 50 (m, 1 H) 7.36 (d, J = 8.3 Hz, 2 H) 7.58 - 7,63 (m. 3 H) 7.66 - 7.69 (m ,1 H) 7.91 - 7,94 (m, 1 H) 7.97 (br t. J = 1.5 Hz, 1 H),
Example 5-24: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.50 - 2.61 (m, 2 H) 2.83 - 2,94 (m. 2 H) 4.43 - 4.52 (m, 1 H) 6.82 (s, 1 H) 7.28 - 7.35 (m, 3 H) 7.44 (t, J * 7.7 Hz, 2 H) 7.58 - 7.65 (m, 4 H) 8.12 (s, 1 H) 8.86 (d, J - 8 3 Hz, 1 H) 9,55 (s, 1 H) 12 25 (br S1 1 H).
Example 5-25: 1H NMR (400 MHz. DMSO-d6) δ ppm 1.66 - 2.47 (m, 10 H) 2.71 - 2 83 (m, 2 H) 3.31 - 3.46 (m, 3 H) 4.18 - 4.49 (m, 2 H) 7.26 - 7.28 (m, 2 H) 7.32 - 7.36 (m, 1 H) 7,43 - 7.47 (m ,2 H) 7.57 - 7.66 (m, 4 H) 7.86 (d. J = 8.3 Hz, 1 H) 12.31 (br s, 2 H),
Example 5-26: 1H NMR (400 MHz, DMSO-d6) δ ppm 1,80 - 2.03 (m, 3 H) 2,27 - 2,31 (m, 1 H) 2.39 - 2.52 (m. 2 H) 2.75 - 2.81 (m, 1 H) 2.85 - 2,89 (m, 1 H) 2.95 - 3.03 (m, 1 H) 3,41 - 3.78 (m, 2 H) 3.90 - 3.99 (m, 1 H) 4.14 - 4.20 (m, 1 H) 4.28 - 4.35 (m, 1 H) 7,28 - 7.37 (m, 3 H) 7.44 - 7,48 (m, 2 H) 7.58 - 7.65 (m ,2 H) 8.45 (br s ,1 H) 12.34 (br s, 1 H), Example 5-27: 1H NMR (400 MHz, CD3OD) 6 ppm 2.38 - 2.54 (m, 6 H) 2.86 (A of ABX, Jab * 13,6 Hz, Jax = 7.6 Hz1 1 H) 2.93 (B of ABX, Jab = 13.6 Hz, Jbx * 6,2 HZ, 1 H) 4.42 - 4.49 (m, 1 H) 7.13 - 7.17 (m, 1 H) 7.31 - 7.37 (m ,3 H) 7.46 - 7.47 (m, 1 H) 7.54 - 7,57 (m, 2 H).
Example 5-28: 1H NMR (400 MHz, CD300) δ ppm 1.49 - 1.71 (m, 6 H) 2.01 - 2.11 (m, 2 H) 2.14 - 2.21 (m, 1 H) 2.44 - 2.56 (m, 3 H) 2.83 (A of ABX, Jab = 13.6 Hz1 Jax = 8.0 Hz, 1 H) 2.91 (B Of ABX1 Jab - 13.6 Hz, Jbx - 6.3 HZ1 1 H) 4.43 - 4.51 (m, 1 H) 7.28 - 7.32 (m, 3 H) 7.38 - 7.42 (m ,2 H) 7.52 (d, J » 8.1 Hz, 2 H) 7.56 - 7.59 (m, 2 H) 7.71 (br d, J * 8.6 Hz, 1 H).
Example 5-29: 1H NMR (400 MHz, CD30D) δ ppm 2.39 - 2.42 (m, 2 H) 2.45 - 2.56 (m, 4 H) 2.87 (A Of ABX, Jab = 13 6 Hz, Jax = 7.8 Hz1 1 H) 2.94 (B of ABX, Jab ~ 13.6 Hz, Jbx = 6,1 Hz, 1 H) 4.44 - 4.51 (m, 1 H) 7.23 (A of AB, J * 8.0 Hz, 2 H) 7.28 (B of AB, J = 8.0 Hz, 2 H) 7,35 (d, J = 7.6 Hz, 1 H) 7.50 - 7.53 (m, 1 H) 7.60 - 7.63 (m, 1 H) 7.75 (d, J - 7.8 Hz, 1 H)
Exampte 5-30: 1H NMR (400 MHz, DMS0-d6) δ ppm 2.45 - 2.56 (m, 2 H) 2.83 - 2.93 (m, 2 H) 4.43 - 4.52 (m, 1 H) 7.18 (s, 2 H) 7.29 - 7.35 (m, 3 H) 7.42 - 7.46 (m, 2 H) 7.58 - 7.65 (m, 4 H) 8.19 (d, J * 8.1 Hz1 1 H) 8.60 (s, 2 H) 12.21 (br s, 1 H).
Example 5-31 : 1H NMR (400 MHz, CD3OD) δ ppm 2.39 - 2.43 (m, 2 H) 2.46 - 2.57 (m, 4 H) 2.90 (A of ABX, Jab = 13.6 Hz1 Jax = 7.8 Hz, 1 H) 2.97 (B of ABX. Jab * 13.6 Hz1 Jbx = 6.1 Hz, 1 H) 4.45 - 4.52 <m, 1 H) 7,37 - 7.39 (m, 2 H) 7,49 - 7.53 (m, 3 H) 7.57 - 7.59 (m ,1 H) 7.70 - 7.74 (m, 1 H) 7.80 - 7.82 (m, 1 H).
Example 5-32: 1H NMR (400 MHz, CD3OD) δ ppm 1.33 - 1.49 (m, 4 H) 1.68 - 1.72 (m, 1 H) 1.79 - 1.83 (m, 1 H) 1.96 - 2.01 (m, 2 H) 2.05 - 2.13 (m, 1 H) 2.17 - 2.25 (m, 1 H) 2.43 - 2.55 (m, 2 H) 2.80 - 2.95 (m, 2 H) 4.42 - 4.49 (m, 1 H) 7.28 - 7.32 (m, 3 H) 7.38 - 7.43 (m, 2 H) 7.52 - 7.59 (m, 4 H).
Example 5-33: 1H NMR (400 MHz, DMS0-d6) δ ppm 2.48 - 2.55 (m, 2 H) 2.84 - 2.96 (m, 2 H) 4.44 - 4.53 (m. 1 H) 6.94 (br », 1 H) 7.30 - 7.35 (m, 3 H) 7.42 - 7.46 (m, 2 H) 7,57 - 7.64 (m, 4 H) 8.17 - 8.60 (br m, 5 H) 12.27 (br s, 1 H). Example 5-34: 1H NMR (400 MHz, CD3OD) δ ppm 1.30 (t, J * 7.0 Hz, 3 H) 2.39 - 2.56 (m, 6 H) 2.82 - 2.93 (m, 2 H) 4.02 (q, J » 7.0 Hz1 2 H) 4.42 - 4.40 (m, 1 H) 6.96 - 7.03 (m, 2 H) 7.23 • 7.28 (m, 4 H) 7.44 (d, J » 8.4 Hz1 2 H).
Example 5-35: 1H NMR (400 MHz, CD3OD) δ ppm 2.14 (s. 3 H) 2.39 - 2.43 (m, 2 H) 2.45- 2.56 (m, 4 H) 2.82 - 2.94 (m, 2 H) 4.02 (q, J = 7.0 Hz1 2 H) 4.42 - 4.49 (m, 1 H) 7.30 - 7.38 (m, 4 H) 7.49 - 7.55 (m, 3 H) 7.80 (br s, 1 H),
Example 5-36: 1H NMR (400 MHz, CD3OD) δ ppm 2.39 - 2.55 (m, 6 H) 2.85 (A of ABX1 Jab « 13.6 Hz, Jax « 7.5 HZ, 1 H) 2.90 (B of ABX1 Jab = 13.6 Hz1 Jbx = 6.3 HZ, 1 H) 4.42 - 4.49 (m, 1 H) 6.86 * 6.92 (m, 1 H) 7.31 (d, J = 8.1 Hz. 2 H) 7.53 - 7.55 (m, 2 H).
Example 5-37: Synthesis of (R)-4^1-carboxy-3-45'-fluoro-2*»methoxytøphenyl-4- yl)propan-2-ylamino)-4-oxobυtanoic acid
Figure imgf000148_0001
To a solution of (R)-4-(4-ethoxy-1-(51-fluoro-2'-methoxybiphenyl-4-yl)-4-oxobutan-2~ylamino)- 4-oxobυtanoic acid (83 mg, 0.192 mmoi) in MeOH (2 mL) is added 1N NaOH (4 mL, 4 mmol) After stirring at room temperature for 2 hours, the crude is concentrated under reduced pressure to remove MeOH and is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN), and then lyophilized to give (R)-4-{ 1 -carboxy-S-β'-fluoro^'-methoxybiphenyM-yOpropan^-ylamino)^- oxobutanotc acid (58 mg). HPLC retention time ~ 1.46 minutes (condition D); MS (m+1) ~ 404.2; 1H NMR (400 MHz, CD3OD) 6 ppm 2.36 - 2.59 (m, 6 H) 2.84 (dd, J*13.4, 6.3 Hz, 1 H) 2.91 (dd. J=13.4, 6.3 Hz1 1 H) 3.75 (s, 3 H) 4.34 - 4.56 (m, 1 H) 6,95 - 7.08 (m, 3 H) 7.26 (d. >8.1 Hz1 2 H) 7.42 (d, J-8.3 Hz, 2 H)
Following compounds are prepared using similar procedure as described in example 5-37:
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Example 5-38: 1H NMR (400 MHz, CDZOD) δ ppm 2.65 (d, >7.1 Hz1 2 H) 2.91 - 3.07 (m, 2 H) 3.26 (s, 3 H) 4,70 (m, 1 H) 7.04 (d, J=8.8 Hz1 1 H) 7.26 - 7.33 (m, 1 H) 7.33 - 7.44 (m, 3 H) 7,47 - 7.56 (m, 3 H) 7.57 (t, J«1.9 Hz, 1 H) 8.02 (dd, J*8.8, 2.5 Hz, 1 H) 8.55 (d, J*1.78 Hz1 1 H).
Example 5»3θ: 1H NMR (400 MHz1 CD3OD) δ ppm 2.36 - 2.60 (m, 6 H) 2.84 {dd, J-13.4, 6.1 Hz, 1 H) 2.91 (dd, J=13.4, 6.1 Hz, 1 H) 3.77 (s, 3 H) 4.34 - 4.58 (m, 1 H) 7.03 (d, J=8.6 Hz1 1 H) 7.18 - 7.31 (m, 4 H) 7.39 (d, J=8.1 Hz, 2 H)
Example 5^0: 1H NMR (400 MHz, DMSOd6) δ ppm 2.51 - 2.70 (m, 2 H) 2.79 - 2.99 (m, 2 H) 3.05 (s, 3 H) 4.41 - 4.62 (m, 1 H) 7.22 (d, J^S.B Hz, 2 H) 7.33 (d, J=8.1 Hz, 2 H) 7.36 - 7.43 (m, 1 H) 7.46 (t, J«7.8 Hz, 1 H) 7.56 - 7.66 (m. 3 H) 7.69 (t. J=1.8 Hz, 1 H) 7.76 (d, J=8.6 Hz1 2 H) 8.30 (d, J=8.3 Hz, 1 H) 10.09 (s, 1 H) 12.24 (s, 1 H)
Example 5-41: 1H NMR (400 MHz, DMSO-Cf6) δ ppm 1.28 (t, J=7.6 Hz, 3 H) 2.51 - 2.60 (m, 2 H) 2.84 - 2.94 (m, 2 H) 2.97 (q, J*7.6 Hz1 2 H) 4.36 - 4.56 (m, 1 H) 7.32 (d, J-8.3 Hz, 2 H) 7.37 - 7.42 (m, 1 H) 7.47 (t, J=7.β Hz, 1 H) 7.60 - 7.66 (m, 3 H) 7.70 (t, >1.8 Hz, 1 H) 8.23 (s, 1 H) 8.60 (d, J*8.3 Hz, 1 H) 12.30 (br. s., 1 H)
Example 5-42: 1H NMR (400 MHz, DMSO-CC6) δ ppm 2.23 - 2.31 (m, 2 H) 2.31 - 2.43 (m, 4 H) 2.76 (d, J=6.6 Hz, 2 H) 4.16 - 4.30 (m. 1 H) 6.87 - 7.02 (m, 2 H) 7.07 (dd, J-9.6, 3.0 Hz, 1 H) 7.21 (d, J=8.3 Hz, 2 H) 7.50 (d. J=8.1 Hz, 2 H) 7.90 (d, J=8.1 Hz, 1 H) 9.51 (br. s.. 1 H)
Example 5-43: 1H NMR (400 MHz, CD3OD) δ ppm 2.33 - 2.60 (m, 6 H) 2.85 (dd, J*13.7, 6.1 Hz, 1 H) 2.94 (dd, J=13.7, 6.1 Hz1 1 H) 3.45 (s, 3 H) 4.35 - 4.57 (m, 1 H) 7.14 (t, J-7.B Hz, 1 H) 7.21 - 7.34 (m, 3 H) 7.38 (dd, J-8.0, 1.6 Hz, 1 H) 7.47 (d, J=8.3 Hz, 2 H)
Example 5-44; 1H NMR (400 MHz, CD3OD) δ ppm 2.64 (d, J-5.8 Hz, 2 H) 3.01 (d. J=6.8 Hz1 2 H) 4.51 - 4.74 (m, 1 H) 7.00 (br. s., 1 H) 7.25 - 7,35 (m, 3 H) 7.40 (t, J-7.6 Hz, 2 H) 7.53 (d, J-8.1 Hz, 2 H) 7.58 (d, J«8.1 Hz, 2 H) 8.21 (br. s., 1 H) Example 5-45: 1H NMR (400 MHz1 CD3OO) ό ppm 2.38 - 2.55 (m, 6 H) 2.85 (del, 7^13.6, 6.3. Hz, 1 H) 2.93 (dd, J-13.6, 6.3, Hz, 1 H) 4.40 - 4.56 (m, 1 H) 7.27 - 7.37 (m, 3 H) 7.40 (t, J=7.8 Hz, 1 H) 7.54 - 7.56 (m, 3 H) 7.60 (t, J=1.8 Hz, 1 H)
Example 5-46: 1H NMR (400 MHz, DMSO-αfδ) δ ppm 2.51 - 2.63 (m, 2 H) 2.84 (dd, J=13.6, 8.3 Hz, 1 H) 2.89 (dd, J=13.6, 8.3 Hz, 1 H) 4.40 - 4.55 (m, 1 H) 7.30 (d, J*8.3 Hz1 2 H) 7.37 - 7.42 (m, 1 H) 7.47 (t, J=7.8 Hz, 1 H) 7.58 - 7.66 (m, 3 H) 7.70 (t, J-1, 9 Hz, 1 H) 8.95 (d, JSsβ.β Hz, 1 H) 12.93 (S1 1 H)
Example 5-47: 1H NMR (400 MHz1 DMSO-Cf6) δ ppm 1.25 (t, J-7.6 Hz, 3 H) 2.51 - 2.59 (m, 2 H) 2.80 (q, J-7.6 Hz, 2 H) 2.84 - 2.94 (m, 2 H) 4.41 - 4.56 (m, 1 H) 7.31 (d, J«8.1 Hz1 2 H) 7.37 - 7.42 (m. 1 H) 7.47 (t, J=7.8 Hz, 1 H) 7.59 (s, 1 H) 7.63 (d, J=8.3 Hz, 3 H) 7.70 (t, J*1.9 Hz1 1 H) 8.45 (d. ,/»8.6 Hz, 1 H) 12,27 (br. s., 1 H)
Example 5-48: 1H NMR (400 MHz1 CD3OD) δ ppm 1.33 (t, J=7.6 Hz, 3 H) 2.64 <d, J=6.8 Hz1
2 H) 2,84 (q, J-7.6 Hz, 2 H) 2.98 (d, J=7.01 Hz, 2 H) 3.72 (s. 3 H) 4.62 - 4.75 (m, 1 H) 6.94 - 7.06 (m, 3 H) 7.27 (d, J=8.1 Hz, 2 H) 7.40 (d, J=8.3 Hz, 2 H) 7.54 (S1 1 H)
Example 5-49. 1H NMR (400 MHz, DMSOd6) δ ppm 2.51 - 2.62 (m, 2 H) 2.84 (dd, J- 13.7, 7.9 Hz, 1 H) 2.91 (dd, J*13.7, 7.9 Hz, 1 H) 3.73 (s. 3 H) 4.42 - 4.55 (m. 1 H) 7.05 - 7.19 (m,
3 H) 7.25 (d, J-8.1 Hz, 2 H) 7.42 (d, J=8.1 Hz, 2 H) 7.73 (S1 1 H) 8.55 (s, 1 H) 8.63 (d, J=8.6 Hz. 1 H)
Example 5-50: 1H NMR (400 MHz1 CD3OD) 6 ppm 2.69 (d, J=6.8 Hz, 2 H) 2.95 - 3.10 (m, 2 H) 4.68 - 4.79 (m, 1 H) 7.21 - 7.33 (m, 1 H) 7.33 - 7.47 (m, 4 H) 7.49 - 7.65 (m, 4 H) 7.76 - 7.97 (m. 2 H) 8.20 - 8,42 (m, 1 H)
Example 5-51 : 1H NMR (400 MHz1 CD3OD) δ ppm 2 62 (d, J=6.6 Hz, 2 H) 2.96 (d, J=7.3 Hz, 2 H) 4.54 - 4.68 (m, 1 H) 7.28 - 7.36 (m, 3 H) 7.40 (t, J-7.7 Hz, 2 H) 7.56 (dd. J-17.2, 7.8 Hz, 4 H)
Example 5-52: 1H NMR (400 MHz1 CD3OD) 6 ppm 2.34 • 2.45 (m, 2 H) 2.45 - 2.59 (m, 4 H) 2.86 (dd. J»13.4, 6.0 Hz1 1 H) 2.93 (dd, >13.4, 6.0 Hz, 1 H) 4.40 - 4.55 (m. 1 H) 7.19 - 7.26 (m. 1 H) 7.34 (d, J=8.1 Hz, 2 H) 7.46 - 7.49 (m, 1 H) 7.51 (t, J=8.0 Hz, 1 H) 7.56 (d, J=8,3 Hz, 2 H) 7.61 (d, J=7,8 Hz1 1 H)
Example 5-53: 1H NMR (400 MHz, DMSO-Cf6) δ ppm 2.04 « 2.26 (m, 2 H) 2.31 - 2.46 (m, 2 H) 2.69 - 2.88 (m, 2 H) 2.94 - 3.21 (m, 2 H) 4.18 - 4.37 (m, 1 H) 7.28 (d, J=7Λ Hz1 2 H) 7.35
- 7.43 <m, 1 H) 7.43 - 7.54 (m, 2 H) 7.63 (d, Λ=8.2 Hz1 3 H) 7.70 (t. J=1.9 Hz, 1 H) 7.98 (dd. J=8.3, 2.3 Hz, 1 H) 12.22 (br. s., 1 H)
Example 5-54; 1H NMR (400 MHz, CO3OD) δ ppm 2.57 (s, 3 H) 2.68 <d, J=6.6 Hz, 2 H) 2.92
- 3.08 (m, 2 H) 4.64 - 4.74 (m, 1 H) 7.25 - 7.33 (m, 1 H) 7.33 - 7.44 (m, 3 H) 7.44 - 7.55 (m, 3 H) 7.57 (t, ./=1.8 Hz, 1 H)
Example 5-55; 1H NMR (400 MHz, CD3OD) δ ppm 2.64 (d, J=6.3 Hz, 2 H) 2.97 (d, J=7.1 Hz1 2 H) 3.74 (S. 3 H) 4.58 - 4.73 (m, 1 H) 6.43 (s, 1 H) 6.96 - 7.08 (m, 3 H) 7.27 (d, J==8.1 Hz, 2 H) 7.42 (d, J«8.1 Hz^ 2 H) 8.71 (d, J=8.3 Hz, 1 H)
Example 5-56; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 - 2.67 (m, 2 H) 2.80 - 2.96 (m, 2 H) 4.38 - 4.54 (m, 1 H) 5.90 (br. s., 1 H) 7.30 (d. J-BΛ Hz1 2 H) 7.35 - 7.42 (m, 1 H) 7.46 (t, «/=7.8 Hz, 1 H) 7.61 (d, J=8.3 Hz, 3 H) 7.69 (t, J=1.9 Hz, 1 H) 8.08 (br. s., 1 H)
Exampte 5-57: 1H NMR (400 MHz1 CD3OD) δ ppm 2.48 - 2.55 (m, 1 H) 2.64 (d, J«6.8 Hz, 1 H) 2.88 - 3.00 (m, 2 H) 4.32 - 4.69 (m, 1 H) 7.26 - 7.35 (m, 3 H) 7.41 (t, J=7.5 Hz, 2 H) 7.49 - 7.65 (m, 4 H)
Example 5-58: 1H NMR (400 MHz, CD3OD) δ ppm 2.62 (d, J=6.6 Hz, 2 H) 2.92 - 3.01 (m, 2 H) 4.59 - 4.64 (m, 1 H) 7.28 - 7.43 (m, 4 H) 7.48 - 7.56 (m, 3 H) 7.59 (t, J~1.9 Hz, 1 H)
Example 5-59: 1H NMR (400 MHz, CD3OD) δ ppm 2.64 (d, J=6.6 Hz, 2 H) 3.01 (d, J=7.1 Hz, 2 H) 4.63 - 4.75 (m, 1 H) 7.05 (d. J=8.1 Hz, 1 H) 7.26 - 7.32 (m, 1 H) 7.35 (d. J=8.3 Hz. 2 H) 7.37 - 7,43 (m, 2 H) 7.44 (d, ,/«1.0 Hz1 1 H) 7.48 (dd, J=8.1, 1.77 Hz, 1 H) 7.52 - 7.60 (m, 4 H) Example 5-60: 1H NMR (400 MHz, CD3OD) δ ppm 2.30 - 2,44 (m, 2 H) 2.44 - 2.64 (m, 4 H) 2.87 (dd, J=13.7, 6.4 Hz, 1 H) 2.95 <dd, J=13.7, 6.4 Hz1 1 H) 4.42 - 4.53 (m, 1 H) 7.27 - 7.52 (m, 8 H)
Example 5-61 : 1H NMR (400 MHz, DMSOd6) δ ppm 2.22 - 2.32 (m, 2 H) 2.32 - 2.44 (m, 4 H) 2.76 (d, >6.6 Hz, 2 H) 4.16 - 4.29 (m. 1 H) 6.82 - 6.88 (m, 1 H) 6.89 - 6.97 (m, 1 H) 7.08 - 7.17 (m, 1 H) 7.17 - 7.28 (m, 3 H) 7.47 (d, J«8.1 Hz, 2 H) 7.90 (d, J=8.1 Hz1 1 H) 9.47 (br. 8., 1 H) 12.14 (br. s., 1 H)
Example 5-62: 1H NMR (400 MHz, DMSO-αfe) 3 ppm 2.22 - 2.31 (m, 2 H) 2.33 - 2.42 (m, 4 H) 2.72 - 2.85 (m. 2 H) 3.72 (s, 3 H) 4.16 - 4.34 (m, 1 H) 6.92 (ddd, J-9.4, 3.79, 1.8 Hz1 1 H) 7.21 - 7.33 (m, 4 H) 7.34 - 7 45 (m, 1 H) 7.92 (d, ./=8.1 Hz1 1 H) 12.14 (br. s., 2 H)
Example 5-63: 1H NMR (400 MHz1 DMS0-d6) δ ppm 2.42 - 2.48 (m, 2 H) 2.85 (d, J~6 8 Hz1 2 H) 4.30 - 4.46 <m, 1 H) 6.99 (s, 1 H) 7.30 (d, J=8.1 Hz1 2 H) 7.36 - 7.42 (m, 1 H) 7.47 (t, J=7.8 Hz1 1 H) 7.63 (d, >8.1 Hz, 3 H) 7.67 - 7.77 (m, 2 H) 10.13 (br. s., 1 H) 10.22 (br. s., 1 H) 12.26 (br. s,, 1 H)
Example 5-64: 1H NMR (400 MHz, CD3OD) 8 ppm 2.35 - 2.60 (m, 6 H) 2.85 (dd, J=13.7, 6.4 Hz, 1 H) 2,93 (dd, J=13.7, 6.4 Hz, 1 H) 3.65 (s, 3 H) 4.37 - 4.58 (m, 1 H) 7.05 - 7.18 (m, 3 H) 7.30 (d, J=8.1 Hz1 2 H) 7.44 (d, J=8.3 Hz1 2 H)
Example 5-65: 1H NMR (400 MHz1 CD3OD) 6 ppm 2.38 - 2.56 (m, 6 H) 2.85 (dd, J-13.4, 7.3 Hz, 1 H) 2.89 (dd, J=13.4, 7.3 Hz1 1 H) 4.40 - 4.52 (m, 1 H) 7,26 - 7.35 (m, 3 H) 7.36 - 7.46 (m, 2 H) 7.52 - 7.61 (m, 3 H)
Example 5-66: 1H NMR (400 MHz, CD3OD) δ ppm 2.31 - 2.58 (m, 6 H) 2.68 - 2.99 (m, 2 H) 3.63 (S, 3 H) 4.33 - 4.56 (m, 1 H) 6,92 - 7.18 (m, 3 H) 7.30 - 7.38 (m, 1 H) 7.38 - 7.46 (m, 2 H)
Example 5-67: 1H NMR (400 MHz, DMSO-Cf6) δ ppm 2.51 - 2.65 (m, 2 H) 2,86 (dd, J=13.7, 8.1 Hz, 1 H) 2.95 (dd, J*13.7. 8.1 Hz, 1 H) 4.42 - 4.61 (m, 1 H) 6.89 - 6.99 (m, 1 H) 7.30 (d, J=8.3 Hz1 2 H) 7.37 - 7.42 (m, 1 H) 7.42 - 7.51 (m, 1 H) 7.62 (d, J=SA Hz, 3 H) 7.69 (t, J-1.8 Hz, 1 H) 7.76 (d, J=9.9 Hz1 1 H) 8.41 (d, J=9.1 Hz, 1 H) 12.26 (br. s., 1 H) 13.40 (s, 1 H) Example 5-68: 1H NMR (400 MHz, DMSO-Cf6) δ ppm 2.51 - 2.57 (m, 2 H) 2.90 (d, J=6.8 Hz, 2 H) 4.34 - 4.52 (m, 1 H) 7.15 (S, 1 H) 7.31 (d, J«8,1 Hz. 2 H) 7.39 (dd, J=7.Q, 1.77 Hz, 1 H) 7.47 (t, J«7.8 Hz, 1 H) 7.59 - 7 66 (m, 3 H) 770 (t. J=1.8 Hz, 1 H) 8.74 (d, J=8.6 Hz, 1 H)
Example 5-69: 1H NMR (400 MHz, CD3OD) 6 ppm 2.61 (d, J=6.β Hz, 2 H) 2.89 - 3.02 (m. 2 H) 4.53 - 4.71 (m, 1 H) 7.16 - 7.37 (m, 4 H) 7.39 (t, J=7.8 Hz1 1 H) 7.45 - 7.57 (m, 3 H) 7.59 (t, J=1.8 Hz, 1 H) 8.20 (d, 1 H).
Example 5-70: 1H NMR (400 MHz, DMSO-de) δ ppm 2.41 - 2.57 (m. 2 H) 2.73 - 2.96 (m, 2 H) 4.35 - 4.46 (m, 1 H) 7.30 (d, ./=8.3 Hz, 2 H) 7.35 - 7.44 (m, 1 H) 7.47 (t, J=7.8 Hz1 1 H) 7.57 - 7.67 (m, 4 H) 7.70 (t, J=1.9 Hz, 1 H) 8.23 (d, J-8.3 Hz, 1 H) 11.14 (S1 1 H) 12.29 (br. s.. 1 H).
Example 5-71: 1H NMR (400 MHz, CD3OD) S ppm 2.58 (dd, J=6.8, 1.8 Hz, 2 H) 2.95 (dd, J=7.Q, 3.4 Hz1 2 H) 4.53 - 4.66 (m, 1 H) 7.27 - 7.36 (m, 3 H) 7.36-7.43 (m, 2H), 7.49-7.57 (m, 3H) 7.59 (t, >1.7 Hz. 1 H).
Example 5-72: 1H NMR (400 MHz, CD3OD) δ ppm 2.60 - 2.71 (m, 2 H), 3.03 (dd, J=6.9, 4.7 Hz, 2 H), 3.28 (s, 3 H). 4.65 - 4.76 (m, 1 H), 7.06 (d, J~8.8 Hz, 1 H), 7.23 - 7.38 (m, 3 H), 7.38 - 7.47 (m, 2 H), 7 50 - 7.64 (m, 5 H), 8.03 (dd, J-8.8, 2.3 Hz, 1 H)1 8.17 (d, 1 H), 8.56 (br. s., 1 H).
Example 5-73: 1H NMR (400 MHz, DMSOd6) δ ppm 2.43 - 2.59 (m. 2 H), 2.82 - 2.95 (m. 2 H), 4.04 - 4.16 (m, 1 H)1 7.30 (d, J-8.3 Hz. 2 H), 7.34 (t, J=7.3 Hz. 1 H), 7.45 (t, J=7.6 Hz, 2 H), 7.59 (d, J=8.1 Hz1 3 H), 7.64 (d, J=8.6 Hz, 2 H), 8.03 (s, 1 H), 12.45 (br, $., 2 H).
Example 6-1: Synthesis of (/?)-3-(bJphenyl-4-ylmethyl)-4-(2-carboxyethy!amJno)-4- oxobυtanoic acid
Figure imgf000166_0001
To a solution of (R)-3-(bipheny)-4-yimethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoic acid (22.1 mg, 0.060 mmol) in THF (0.6 mL) and methanol (0.1 mL), aqueous 1M NaOH (0.12 mL, 0.12 mmol) is added at room temperature. After stirring for 3 hours, additional aqueous 1M NaOH {0.12 mL, 0.12 mmoi) is added. The reaction mixture is allowed to stir for 30 minutes and quenched with 0.5 mL of aqueous 1M HCI and 0.5 mL of brine. The mixture is extracted twice with ethyl acetate, and the organic layer is concentrated under reduced pressure to give (f?)-3-(biphenyl-4-ylmethyl)-4-(2-carboxyethylamino)-4-oxobutanoic acid (16.4 mg). HPLC retention time * 1.04 minutes (condition A); MS (m+1) ~ 356.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.13-2.31 (m, 3 H) 2.59 - 2,65 (m, 1 H) 2.81 - 2.90 (m, 2 H) 3.12 - 3.27 (m, 2 H) 7.26 (d, 2 H, J « 8 Hz) 7.34 (t, 1 H, J = 7.4 Hz) 7.45 (t, 2 H, J « 7.7 Hz) 7.57 (d, 2 H, J a 8.1 Hz) 7.63-7.65.
Example 7-1: Synthesis of (R)-3-biphβnyl-4-ylmethyl-N-carboxymethyl-βuccinamic acid
Figure imgf000166_0002
A solution of (RHert-butyl 3-(biphenyl~4-ylmethyl)-4-(2-tert-butoxy-2-oxoethylamino)-4- oxobutanoate (40 mg, 0.088 mmo!) and TFA (0.5 mL, 6.49 mmoi) in DCM (1.5 mL) is allowed to stir for 2 hours at room temperature. The reaction is concentrated under reduced pressure, and the obtained residue is suspended in DCM (0.5 mL) and heptane (2 mL), and collected on a funnel, giving (R)-3-biphenyM-ylmethyl-N-carboxymethyl-succinamic acid (9.6 mg). HPLC retention time « 126 minutes (condition A); MS (m+1) = 342.0; 1H NMR (400 MHz1 CD3OD) δ ppm 2.39 (dd, J=16.67, 5.31 Hz, 1 H) 2.63 - 2.82 (m. 2 H) 2.98 - 3.14 (m, 2 H) 3.84 and 3.95 (AB, 2 H, J = 17.8 Hz) 7.26 - 7.33 (m, 3 H) 7.40 (t, J=7.71 Hz, 2 H) 7,56 (dd. J=19.96, 8.08 Hz, 4 H),
Following compounds are prepared using similar procedure as described in example 7-1:
Figure imgf000167_0002
Example 7-2: 1H NMR (400 MHz, OMSO-d6) δ ppm 1.51-1.58 (m, 2 H) 2.12 - 2.21 (m, 3 H) 2.49- 2,65 (m, 2 H) 2.81 - 2.89 (m, 2 H) 2.94 - 3.08 (m, 2 H) 7.26 (d, 2 H. J * 8.1 Hz) 7.32 - 7.36 (m, 1 H) 7.43-7.46 (m, 2 H) 7.57 (d. 2 H, J * 8.0 Hz) 7.63-7.65 (m, 2H).
Example 8-1 : Synthesis of (R)-4-|2-biphenyJ-4-ylniethyl-3-carboxy-propionylamino>-2- methyl-pentanoic acid
Figure imgf000167_0001
To a stirred solution of 2-biphenyl-4-ylmethyl-succinic acid 4-tert-butyl ester (100 mg, 0.29 mmoi) in DMF (10 mL) is added HOBt (45 mg, 0.29 mmol) and EDCI (56 mg, 0.29 mmol) and the mixture is stirred at room temperature for 10 minutes then (2R,4R)-4-amino-2~ methyl'pentanoic acid ethyf ester trifluoroacetate (47 mg, 0.29 mmol) and triethylamine (89 mg, 0.87 mmol) is added and the mixture is stirred at room temperature for 5 hours. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is washed with water, brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure to give (2R,4R)~7-btphenyi-4-yimethyl-2,4-d/methyl-6-oxo- nonanedioic acid 9-tert-butyl ester 1 -ethyl ester. Next, to a solution of (2R,4R)-7-bipheny}-4-ylmethyt-2l4-ctimethyl-6-oxo-nonanecliotc acid 9- tert-butyl ester 1 -ethyl ester EtOH (4 mL) is added aqueous 1M NaOH (4 mL) and the mixture is stirred at room temperature for 30 minutes. The mixture is acidified to pH 2-3 with aqueous 1M HCl and Is extracted with ethyl acetate. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water {0.1% TFA). Lyophilization of the proper fractions furnished (R)-4-(2-bipher\y!-4- ylmethyl-3-carboxy-propionylamino)-2-methyl-pentanoic acid. HPLC retention time « 1.13 minutes (condition C); MS 398.2 (M+1); 1H- NMR (400 MHz, DMSO-d6) δ ppm 0.93 (m, 6H), 1.23 (m, 1H), 1.59 (m, 1H), 2.17 (m, 1H)1 2.63 (m, 1H), 2.82 (m, 1H), 3.72 (m, 1H), 7.27 (m, 2H), 7.33 (m, 1H), 7.45 (m, 2H), 7.56 (m, 2H), 7.62 (m. 2H), 7.71 (m, 1H)1 12.07 (s, 1H).
Example 9>1: Synthesis of (Λ)-4-biphenyl-4-yl-3-{(1W«tetrazoJe-S-carbonyl)-am^°J- butyric acid
Figure imgf000168_0001
To a mixture of (R)-3-[{1 -benzyl- 1H-tetrazofe-5-carbonyl)-amino3~4-biphenyl-4-yl-butyric acid ethy! ester and (R)-3-[{2-benzyl'2H-tetra2ole-5-carbonyl)-amino)-4-biphenyl-4-yl-butyric acid ethyl ester (180 mg, 0.383 mmoi) in EtOH (1 mL) and THF (1 mL) is added aqueous 1M LiOH (2 mL). After stirring for 0.5 hour, the reaction mixture is acidified with aqueous 1M HCI. The mixture is extracted with ethyl acetate, dried over Na2SO4, and concentrated under reduced pressure. The residue is dissolved in MeOH and hydrogenated with 10% Pd/C at room temperature for 3 hours and at 40°C for 2 hours, The reaction mixture is concentrated and purified by reverse phase HPLC to give (R)-4-biphenyl~4-y!-3-((1H-tetrazole-5-carbony!)- aminoj-butyric acid. HPLC retention time = 1.18 minutes (condition D); MS (m+1) ~ 352; 1H NMR (400 MHz1 DMSO-d6) i ppm 2.56 (dd, J«5.81 , 15.92Hz1 1H)1 2.67 (dd, J=7.58, 15.92H2, 1H), 2.85-2.99 (m, 2H), 4.55-4.64 (m, 1H), 7.26-7.35 (m, 3H). 7.43 (dd, J=7.83, 7.83Hz, 2H), 7.56 (d, J=8.08Hz, 2H), 7.62 (d, J*7.07Hz, 2H), 9.28 (d. 8.84Hz, 1H), 12.28 (S, 1H).
Example 10-1: (R)-4>bipheyl-4>yl-3^3-1H»tetrazoi»S-yl«propionylamino)-butyric acid
Figure imgf000169_0001
To a solution of (R)-4-biphenyl-4-y!-3-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yi]-propionylamino}- butyric acid ethyl ester (137 mg, 0.297 mmol) in DCM (8 rnL) at room temperature is added DBU (1.507 mL, 10.00 mmol) and the mixture is stirred at room temperature for 2 hours. The reaction is extracted with DCM. The combined organic layer is washed with saturated NH4CI1 brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced. The obtained residue is purified by flash chromatography (silica gel, 2% to 10% EtOH/DCM) to give (R)-4-bipheyl-4-yl-3-(3-1H-tetrazoi-5-yl-propionylamino)-butyπc acid ethyl ester (37 mg). To the obtained ester in EtOH (2 mL) at room temperature is added aqueous 1M NaOH (1 mL, 1.0 mmol) and the mixture is stirred at room temperature for 1 hour. To the reaction is added 1 mL of aqueous 1M HCI to pH-4, and the mixture is purified by reverse phase HPLC [30% to 60% aceiorHtrile-H2O (0.1% TFA)] to give (R)~4-bipheyl-4-yl-3-(3-1 H- tetrazo!«5-y!-propionylamino)-butyric acid. HPLC retention time ~ 1.24 minutes (condition C); MS (m+1) = 380: 1H NMR (400 MHz, DMSO-cW δ ppm 2.37 (dd, J=6.7, 2.1 Hz, 2 H), 2.53 (t. J=7.6 Hz, 2 H)1 2.69 - 2.82 (m, 2 H), 3.02 (t, J=7.7 Hz, 2 H), 4.17 - 4.29 (m, 1 H). 7.22 (d, J=8.3 Hz, 2 H), 7.34 (tt. J*7.3, 1.3 Hz, 1 H), 7.42 - 7.48 (m, 2 H), 7.57 (d, J-8.3 Hz1 2 H), 7.64 (dd, J=8.2, 1 ,1 Hz1 2 H), 8.00 (d. J-Q.I Hz1 1 H), 12.21 (br. s., 1 H), 15.92 (br. β., 1 H). Chirai HPLC retention time = 5.64 mtn. Column: Daicel CHIRALCEL OJ-H (4.6x100mm); flow rate = 1 ml/min.: eluent: EtOH(containing 0.1% TFA)/heptane = 2/8. Example 11-1: Synthesis of (R)-4-(1-carboxy-3-(3'-chlorobJphenyl-4-yf)propan-2- yiamino)-4-oxobutanoic acid
Figure imgf000170_0001
To a solution of (R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ytamino)-4-oxobutanoic acid (110 mg, 0.263 mmot) in THF (2 mL) and methanol (0.2 mL), aqueous 1M NaOH solution (1.053 mL, 1.053 mmol) is added at room temperature. After stirring for 1 hour, the reaction is quenched with 0.1 M aqueous HCI, and the solution is diluted with DCM (15 ml) and allowed to stir for 1.5 hours. The precipitated soiid is collected on a funnel, washed with water, DCM, heptane and then DCM in that order, and dried under reduced pressure to (R)- 4-(1-carboxy-3-(3'-ch!orobiphenyM-yl)propan-2-ylamtno)-4-oxobutanoic acid (66 mg). HPLC retention time = 0.67 minutes (condition 8); MS (m+1) » 390.0; 1H NMR (400 MHz, CD3OD) δ ppm 2.39-2.55 (m, 6 H) 2.86 (A of ABX, Jsb « 13.6 Hz, Jax « 7.6 Hz, 1 H) 2.92 (B of ABX, Jab - 13.6 Hz, Jbκ ~ 6.2 Hz1 1 H) 4.42 - 4.49 (m, 1 H) 7.30 - 7.34 (m, 3 H) 7.40 (t, J « 7.4 Hz, 1 H) 7.51 - 7.56 (m, 3 H) 7.60 (t, J = 1.8 Hz, 1 H).
Following compounds are prepared using similar procedure as described in example 11-1:
Figure imgf000170_0002
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Example 11-2: 1H NMR (400 MHz, CD3OD) δ ppm 1.76 - 1.83 (m, 2 H) 2.15 - 2.21 (m, 4 H) 2.49 (A of ABX1 Jab = 15.7 Hz, J3, = 7.3 Hz, 1 H) 2.53 (B of ABX, JBb - 15.7 Hz, Λx = 6.1 Hz, 1 H) 2,83 (A of ABX, Jab » 13.6 Hz, J8x = 8.3 Hz, 1 H) 2.93 (B of ABX, J^ = 13.6 Hz, J* - 5.8 Hz1 1 H) 4.46 - 4.53 (m, 1 H) 7.30 - 7.33 (m, 3 H) 7.39 (t,, J » 7.8 Hz, 1 H) 7.51 - 7.55 (m. 3 H) 7.59 ~ 7.60 (m. 1 H).
Example 11-3: 1H NMR (400 MHz, CD3OD) δ ppm 1.77 - 1.84 (m, 2 H) 2.16 - 2.23 (m ,4 H) 2.39 - 2,42 (m, 2 H) 2.49 (A of ABX, Jab = 15.6 Hz, JβK - 7.5 Hz. 1 H) 2.53 (B of ABX, J3* = 15.6 Hz, Jbx = 6.1 Hz, 1 H) 2.83 (A of ABX, Jab * 13.6 Hz, J9x = 6.1 Hz1 1 H) 2.91 (B of ABX, JaB = 13.6 Hz, Jbχ * 6 3 Hz, 1 H) 3.75 (s, 3 H) 4.46 - 4.53 (m. 1 H) 6.97 - 7.04 (m, 2 H) 7.26 (d, J = 8.1 Hz, 2 H) 7.42 (d. J « 8.1 Hz1 2 H).
Example 11-4: 1H NMR (400 MHz, CD3OD) δ ppm 1.77 ■ 1.84 (m. 2 H) 2,16 - 2.24 (m, 4 H) 2.49 (A of ABX, J3b = 15,6 Hz, J3x = 7.5 Hz, 1 H) 2.54 (B of ABX, Jah * 15.6 Hz, Jbx = 6.1 Hz, 1 H) 2.83 (A of ABX. Jab - 13.6 Hz, J3x = 8.2 Hz1 1 H) 2.91 (B of ABX, Jab = 13.6 Hz, Jb* - 6.1 Hz, 1 H) 3.77 (S, 3 H) 4 45 - 4.52 (m, 1 H) 7.03 (d, J ~ 8.6 Hz, 1 H) 7.24 - 7.28 (m, 3 H) 7.39 - 7.41 (m, 2 H).
Example 11-5: 1 H NMR (400 MHz, CD3OD) δ ppm 1.49 - 1.56 (m, 4 H) 2.13 (t, J = 6.8 Hz, 2 H) 2.23 (t, J a 6.9 Hz, 2 H) 2.45 - 2.56 (m, 2 H) 2.80 - 2.86 (m, 1 H) 2.91 - 2.96 (m, 1 H) 4.46 - 4.53 (m. 1 H) 7.31 - 7.33 (m, 3 H) 7.40 (t. J = 8.0 Hz, 1 H) 7 52 - 7.55 (m, 3 H) 7 59 (br t, J « 1.8 Hz, 1 H).
Example 11-6: 1H NMR (400 MHz, CD3OD) δ ppm 2.39 - 2.57 (m, 4 H) 2.80 (A of ABX, Jab ~ 13.6 Hz, J3K = 8.1 Hz, 1 H) 2,89 (B of ABX, Jβb = 13.6 Hz. J^ ~ 6.1 Hz1 1 H) 3.04 (t, J = 7.1 Hz, 2 H) 3.75 (S, 3 H) 4.40 ~ 4.47 (m, 1 H) 7.27 - 7.29 (m ,2 H) 7.32 - 7.35 (m, 1 H) 7.41 (t, J = 7.8 Hz, 1 H) 7.51 - 7.54 (m, 3 H) 7.59 - 7.60 (m, 1 H) 7.83 - 7.84 (m, 1 H) 8 28 (br d, J = 7.1 Hz, 1 H) 8.55 <d. J = 5.6 Hz, 1 H) 8.62 (s, 1 H) Example 11-7: 1H NMR (400 MHz, CD3OD) 5 ppm 2.47 (A of ABX, JΛ = 15.7 Hz, J3* * 7.7 HZ, 1 H) 2.54 (B of ABX, Jab ~ 15.7 Hz, Jbx « 5.8 Hz, 1 H) 2.64 - 2.75 (m, 2 H) 2.80 (A of ABX, J* = 13.7 Hz1 JΆX = 8.3 Hz, 1 H) 2.92 (B of ABX, Jab = 13.7 Hz, Jbx « 5.9 Hz. 1 H) 3.17 - 3.21 (m, 2 H) 4.43 ~ 4.50 (m, 1 H) 7.28 - 7.35 (m, 3 H) 7,39 - 7.43 (m, 1 H) 7.51 - 7.54 (m, 3 H) 7.59 (br t, J = 1.9 Hz, 1 H) 7.69 - 7.75 (m, 2 H) 8.29 - 8.32 (m. 1 H) 8.61 (d, J = 4.6 Hz, 1 H).
Example 11-8: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.82 - 1.89 (m, 2 H) 2.29 (t, J * 7.3 Hz, 2 H) 2.56 (A of ABX, Jab ~ 16.4 Hz, J3x = 5.6 Hz1 1 H) 2.64 (B of ABX, JΛ = 16.4 Hz, Λ* s 5.1 Hz. 1 H) 2.95 (A of ABX, Jab = 13.8 Hz, Jax * 7.6 Hz1 1 H) 2.99 (B of ABX, Jab = 13.8 Hz, J0x = 7.2 Hz, 1 H) 3.30 (s, 3 H) 3.38 (t, J ~ 5.9 Hz, 2 H) 4.10 (q, J « 7.1 Hz, 2 H) 4.52 - 4.57 (m, 1 H) 6.59 (br d, J « 8.6 Hz7 1 H) 7.26 • 7.37 (m, 4 H) 7.42 - 7.45 (m, 1 H) 7.48 - 7.52 (m, 2 H) 7.55 (br t, J = 1.6 Hzt 1 H).
Example 11-9: 1H NMR (400 MHz, CD3CN+D2O) δ ppm 2,43 - 2.56 (m, 2 H) 2.71 - 2.91 (m, 4 H) 3.21 - 3.34 (m. 2 H) 4.39 - 4.46 (m, 1 H) 7.27 (d, J ~ 8.3 Hz1 2 H) 7.34 - 7.49 (m, 7 H)
7.55 - 7.56 (m, 1 H) 7.65 - 7.70 (m, 2 H).
Example 11-10: 1 H NMR (400 MHz, CD3OD) δ ppm 2.38 - 2.41 (m, 2 H) 2.47 - 2.58 (m, 4 H) 2.85 - 2.90 (m, 1 H) 2.99 - 3.04 (m, 1 H) 4.48 ~ 4.55 (m, 1 H) 7.32 - 7.44 (m, 5 H) 7.53 -
7.56 (m, 1 H) 7.62 - 7.63 (m, 1 H).
Example 11-11: 1H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO-d6): δ ppm 2.44-2.52 (m, 2H)1 2.83-2.85 (d, J=6.82 Hz, 2H)1 4.29-4.38 (m, 1 H)1 7.28-7.30 (d, J~8.34 Hz, 2H), 7.40-7.43 (t, J=7.83 Hz, 1H), 7.62-7.65 (m, 3H), 7.71-7.72 (t, J«1.77 Hz, 1 H)1 9.42-9.45 (M, 1H), 12.32 (8. 1H).
Example 11-12: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54-2.59 (m. 1H), 2.64-2.70 (m, 1H), 2.88-2.93 (m, 1H), 2.98-3.03 (m, 1H), 4.56-4.63 (m, 1H), 7.30-7.32 (m, 2H), 7.37-7.40 (m, 1H), 7.43-7.47 (t, J=7.83 Hz, 1H), 7.59-7.61 (m. 3H), 7.67-7.68 (t, J=2.02 Hz1 1H)1 8.32 (d, J=1.26 Hz, 1H), 9.17-9.19 (d, J*9,09 Hz, 1 H), 9.50 (d, J-1.52 Hz, 1H), 12.34 (s, 1H), 14.14 (s, 1H). Example 11-13: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.46-2.60 (m, 2H), 2.84-2.96 <m, 2H),
4.51 (m. 1H), 7.31 (d, J=8.34 Hz, 2H)1 7.38-7.41 (m, 1H). 7.46 (t, 1H), 7.62 (d. J-8.34 Hz1 3H), 7.69 (t, 1H).
Example 11-14: 1H NMR (400 MHz, DMSO-d6) δ ppm ) 2.75 - 2.99 (m, 1 H) 4.47 (d, J-7.58 Hz, 1 H) 6.49 (S1 1 H) 7.30 (d, J=8.34 Hz, 1 H) 7.37 - 7.43 (m, 1 H) 7.47 (t, J=7.83 Hz, 1 H) 7.63 (d, J-8.08 Hz, 2 H) 7.70 (t, J=1.77 Hz, 1 H) 8.80 (d, J=8.59 Hz, 1 H) 11.69 (s, 1 H) 12.04 - 12.58 (m. 1 H).
Example 11-15: 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.81 - 2.96 (m, 2 H) 4.42 - 4.55 (m. 1 H) 7.31 (d, J=8.34 Hz, 2 H) 7.36 - 7.43 (m, 1 H) 7.47 (t, J=7.83 Hz, 1 H) 7.63 (d, J=8.34 Hz, 4 H) 7.69 (t, J=1.77 Hz1 1 H) 7.72 (S1 1 H) 8.54 (s, 1 H) 8.60 (d. J=8.59 Hz1 1 H) 12.29 (br. s., 1 H).
Example 11-16: 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.53 - 2.64 (m, 2 H) 2.84 - 2.93 (m, 2 H) 4.41 - 4.59 (m, 1 H) 7.00 (d, J-2.02 Hz, 1 H) 7.31 (d, J«8.0β Hz, 2 H) 7.37 - 7.42 (m. 1 H) 7.47 (t, J-7.83 Hz1 1 H) 7,58 - 7.65 (m, 3 H) 7.70 (t, J-1.77 Hz1 1 H) 8.72 (d, J*1.77 Hz, 1 H) 8.95 (d, J=8.59 Hz, 1 H) 12.31 (br. s., 1 H).
Example 11-17: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.46-2.60 (m, 2H), 2.83-2.98 (m, 2H),
4.52 (m, 1H), 6.61 (d, J-2.27 Hz, 1H), 7.31 (d, J=8.34 Hz, 2H)1 7.37-7.42 (m, 1 H), 7.46 (t, 1H)1 7.62 (d, J=8.34 Hz, 3H), 7.69 (t. 1H)1 7.74 (d, J-2.02 Hz, 1H)1 8.13 (d, J-8.84 Hz, 1H).
Example 11-18: 1H NMR (400 MHz1 DMSO-d6) δ ppm 2.48-2.62 (m, 2H), 2.84-2.96 (m. 2H)1 4.52 (m, 1H), 7.16 (d. J=3.54 Hz, 1H), 7.27 (d, J=3.79 Hz, 1H), 7.31 (d, J-8.34 Hz, 2H), 7.38-7.41 (m, 1H), 7.47 (t. 1H)1 7.63 (d, J=8.34 Hz, 3H). 7.70 (t, 1H), 8.59 (d, J=8 59 Hz, 1H).
Example 11-19. 1H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO-d6): δ ppm 2.54-2.67 (m, 2H), 2.88-2.92 (m, 1H), 2.99-3.05 (m, 1H). 4.53-4.62 (m, 1H), 7.31-7.33 (m, 2H), 7.37-7.39 (m, 1H). 7.43-7.47 (t, J = 7.58 Hz, 1H), 7.60-7.62 (m, 3H), 7.68 (m, 1H)1 7.86-7.87 <d, J=4.55 Hz. 1H). 8.30 (S1 1H), 8.62-8.63 (d. J=4.80 Hz, 1H)1 8.80-8.83 (d. J=9.09 Hz, 1H). Example 11-20: 1H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO-d6): δ ppm 2.50-2.53 (m, 1H), 2.56-2.59 (t, J==6.32 Hz, 1H), 2.90-2,98 (m, 2H), 4.51-4.58 (m, 1H), 7.33- 7.35 (d, J=8.34 Hz, 2H), 7.39-7.42 (m, 1H), 7.45-7.49 (t, J=7.83 Hz, 1H), 7.61-7.65 (m, 3H)1 7.69-7.70 (t, J=1.77 Hz1 1H)1 7.90-7.91 (dd, J-1.77 Hz, 5.05 Hz, 1H), 8.38-8.39 (m, 1H), 8.83-8.85 (dd, J-0.76 Hz, 5.05 Hz, 1H), 8.91-8.93 (d, J=8.34 Hz, 1H).
Example 11-21: 1 H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO-d6): δ ppm 2.45-2.55 (m, 1H)1 2.59-2.67 (m, 1H), 2.88-2.93 (m, 1H), 2.99-3.05 (m, 1H), 4.51-4,61 (no, 1H)1 7.32-7.34 (d, J=8.08 Hz, 2H), 7.37-7.40 (m, 1H)1 7.44-7,48 (t, J=7.58 Hz1 1H), 7.60-7.62 (t, J-7.83 Hz1 2H)1 7.69 (s, 1H), 7.77 (S, 1H), 8.86-8.87 (d. J=4.04 Hz, 1H), 9.06 (s, 1H).
Example 11-22: 1 H NMR (400 MHz, DMSO~d6): δ ppm 2.49-2.53 (m, 2H), 2.90-2.92 (d, J=6.82 Hz, 2H), 4.42-4.51 (m, 1H), 6.72-6J3 (d, J-2.27 Hz, 2H), 7.32-7.34 (m, 2H), 7,39- 7.42 (m, 1H), 7.45-7.49 (t, J = 7.83 Hz1 1H), 7.62-7.66 (m, 3H), 7.70-7.71 (t, J=1.77 Hz, 1H), 8.27-8.29 (d, J=8.08 Hz, 1H), 11.96 (s, 1H), 12.33 (s, 1H), 12.75 (s, 1H).
Example 11-23: 1H NMR (400 MHz1 DMSO-d6): 1H NMR (400 MHz, DMSO-d6): δ ppm 2.44-2.55 (m, 2H), 2.79-2,89 (m, 2H)1 4.29-4.38 (m. 1H), 7.27-7.29 (d, J=8.08 Hz, 2H), 7.39- 7.42 (m, 1H), 7.45-7.49 (t, J=8.08 Hz, 1H), 7.62-7.64 (d, J«8.08 Hz1 3H), 7.70-7.71 (m, 1H), 8.85-8.87 (d, J=9.09 Hz, 1H), 12.30 (s, 1H).
Example 11-24: 1H NMR (400 MHz, DMSO-dδ) δ ppm 2.46-2.60 (m, 2H), 2.84-2.96 (m, 2H), 4.51 (m, 1H)1 7.15 (m, 2H), 7.44-7.52 (m, 3H), 7.62 (d, J=8.34 Hz, 2H), 8.38 (d, broad, J-7.58 Hz, 1H).
Example 11-25: 1H NMR (400 MHz, DMSO-d6): δ ppm 2.54-2.59 (m, 1H), 2.64-2.70 (m, 1H), 2.88-2.93 (m, 1H), 2.98-3.03 (m, 1H), 4.56-4.65 (m, 1H), 7.13-7.18 (m. 1 H), 7.30-7.32 (d, J~8,34 Hz, 2H), 7.45-7.48 (m, 3H), 7.60-7.62 (d, J=8.34 Hz, 2H)1 8.31-8.32 (d, J=1,26 Hz, 1H), 8.17-8.19 (d, J=9.09 Hz, 1H), 8.49 (d, J-1.26 Hz, 1H), 12.32 (s, 1H), 14.10 (s, 1H).
Example 11-26: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 - 2 62 (m, 2 H) 2.83 - 2.92 (m, 2 H) 4.47 (d, J=7.07 Hz, 1 H) 6.49 (s, 1 H) 7.11 - 7.21 (m, 1 H) 7.30 (d, J=8.34 Hz, 2 H) 7.42 - 7.55 (m, 3 H) 7.64 (d, J=8.34 Hz, 2 H) 8.80 (d, J-8.59 Hz, 1 H) 11.68 (br. s., 1 H) 12.30 (br. s., 1 H). Example 11-27: 1H NMR (400 MHz, DMSO-d6) 6 ppm 2.51-2.57 (m, 1H)1 2.64-2.70 (m, 1H), 2.84-2.89 (dd, >6.06 Hz, 1H). 2.96-3.01 (dd, J-7.83 Hz, 1H), 3.72 (S1 3H), 4.54-4.63 (m, 1H)1 6.96-7.00 (m, 1H)1 7.06-7.08 (dd, J=0.76 Hz, 1H), 7.22-7.24 (m, 3H), 7.28-7.32 (m, 1H)1 7.35-7.38 (m, 2H), 8.33-8.34 (d, J=1.26 Hz1 1H), 9.16-9.18 (d, >9.09 Hz1 1H), 9.49 (d, J~1.52 Hz, 1H), 12.31 (S1 1H), 14.13 (S, 1H).
Example 11-28: 1H NMR (400 MHz1 DMSO-d6) δ ppm 2,52-2.60 (m, 2H), 2.73 (s, 1H), 2.89 (S, 1H), 2.81-2.95 (m, 2H), 3.74 (s, 3H)1 4.50 (m, 1H), 7.00 (t, 1 H), 7.08 (d, J=8.34 Hz, 1H), 7.15 (S, broad, 1H), 7.23-7.26 (m, 3H), 7.29-7.33 (m, 1H), 7.38 (d, J=8.08 Hz, 2H), 8.39 (d, broad, J-7.07 Hz, 1H).
Example 11-29: 1H NMR (400 MHz1 CD3OD) δ ppm 1.33 (t, J=7.6 Hzx 3 H) 2.66 (d, J=6.8 Hz, 2 H) 2.84 (q, J=7.6 Hz1 2 H) 2.98 (dd, J=13.6, 8 1 Hz, 1 H) 3.03 (dd, >13.6, 6.6 Hz. 1 H) 4.64 - 4.76 (m, 1 H) 7,24 - 7.37 (m, 6 H) 7.40 - 7.45 (m, 1 H) 7.53 (s, 1 H).
Example 11-30: 1H NMR (400 MHz1 DMSO-d6) δ ppm 2.40 - 2.51 (m, 2 H) 2.79 - 2.90 (m. 2 H) 4.29 - 4,38 (m, 1 H) 6.47 (d. J = 15.7 Hz1 1 H) 6.88 (d, J = 15.7 Hz 1 H) 7.28 - 7.30 (m, 2 H) 7.39 ~ 7.41 (m, 1 H) 7.47 (t, J ~ 8.0 Hz, 1 H) 7.62 - 7.65 (m, 2 H) 7.70 - 7.71 (m, 1 H) 8.54 (d, J = 8.1 Hz. 1 H) 7.31 (d, J = 8.3 HZ, 2 H) 7.40 - 7.43 (m, 1 H) 7.47 - 7.50 (m, 1 H) 7.62 - 7.65 (m, 3 H) 7,69 - 7.71 (m, 1 H) 8,54 (d, J « 8.1 Hz, 1 H)
Example 11-31 : 1H NMR (400 MHz, DMSO-cfe) δ ppm 2.22 (s, 3 H) 2.43 - 2.49 (m, 1 H) 2.52 - 2.60 (m, 1 H) 2.84 (dd, J=13.6. 6.1 Mz, 1 H) 2.94 (dd. J=13.6, 8.1 Hz, 1 H) 4.39 - 4.58 (m, 1 H) 6.33 (s, 1 H) 7.30 (d, J=8.3 Hz, 2 H) 7.36 - 7.42 (m, 1 H) 7.46 (t, J-7.8 Hz, 1 H) 7,61 (d, J=8.3 Hz, 3 H) 7.69 (t, J«1 ,9 Hz1 1 H) 8.02 (d, J~7,8 Hz, 1 H).
Example 11-32; 1 H NMR (400 MHz, DMSO-cfe) δ ppm 2.61 - 2.56 (m, 2 H) 2.89 (d, J«6.8 Hz, 2 H) 3.31 (S1 3 H) 4.33 - 4.57 (m, 1 H) 7.31 (d, J=8.1 Hz, 2 H) 7.37 - 7.42 (rrt, 1 H) 7.46 (t, J-7.8 Hz1 1 H) 7.60 - 7.66 (m, 3 H) 7.69 {t, J-1.8 Hz, 1 H) 8.15 (S1 1 H) 8.50 (d, v/=8,3 Hz, 1 H) 12,24 (br. s., 1 H).
Example 11-33: 1H NMR (400 MHz, DMSOd6) δ ppm 2.52 - 2.60 (m, 2 H) 2.66 (s, 3 H) 2.93 (d, J=6.8 Hz, 2 H) 4.43 - 4.63 (m, 1 H) 7.33 (d, J=8.1 Hz, 2 H) 7.36 - 7.42 (m, 1 H) 7.46 (t, J-7.8 Hz, 1 H) 7.58 - 7.66 (m, 3 H) 7.69 (t, J=1.8 Hz, 1 H) 8.74 (d, J-8.3 Hz, 1 H) 8.98 (s, 2 H) 12.28 (br. s., 1 H).
Example 11-34; 1H NMR (400 MHz1 MeOD) δ ppm 2.15 (s, 3 H) 2.67 (d, J=6.6 Hz, 2 H)
2.98 (dd, J-13,9, 8.3 Hz, 1 H) 3.03 (dd, J=14.1, 6.8 Hz, 1 H) 4.62 - 4.77 (m, 1 H) 5.57 (s, 1 H) 6.16 (S, 1 H) 7.27 - 7.32 (m, 1 H) 7.32 - 7.41 (m, 3 H) 7.4$ - 7,54 (m, 3 H) 7.56 <t, J=1.8 Hz1 1 H) 7.65 (s, 1 H) 8.55 (d, J=8.6 Hz, 1 H).
Example 11-35: 1H NMR (400 MHz. CD3OD) δ ppm 2.42 (s, 3 H) 2.63 (d, J=6.3 Hz, 2 H)
2.99 (d, J=7.1 Hz1 2 H) 4.59 - 4.73 (m, 1 H) 7,25 - 7.30 (m, 1 H) 7.30 - 7.37 (m, 3 H) 7.41 - 7.50 (m. 3 H) 7.53 (t, J=1.8 Hz, 1 H) 8.15 (s, 1 H).
Example 11-36: 1H NMR (400 MHz1 DMSO-d6) δ ppm 2.51 - 2.61 (m, 2 H) 2.87 (dd, J«13.1 , 5.6 Hz, 1 H) 2.94 (dd. J=13.4, 7,6 Hz. 1 H) 4.41 - 4.60 (m, 1 H) 7.29 - 7.38 (m, 3 H) 7.45 (ddd, J=8.7, 4.2, 2.8 Hz, 1 H) 7.49 (d, J~Q,β Hz, 2 H) 7.56 (dd, J=6.8, 2.5 Hz, 1 H) 7.71 (s, 1 H) 8.53 (s. 1 H) 8.59 (d, J=8.6 Hz1 1 H) 12.26 (br. s., 1 H).
Example 11-37: 1H NMR (400 MHz, CD3OD) δ ppm 1 ,32 (t, J=7.6 Hz, 3 H) 2.66 (d, J«6.8 Hz, 2 H) 2.83 (q, J«7.6 Hz, 2 H) 2.98 (dd, J=13.6, 7.8 Hz, 1 H) 3.03 (dd, J=14.7, 6.8 Hz, 1 H) 4.61 - 4.80 (m, 1 H) 7.13 {dd, J=18.9, 10.1 Hz, 1 H) 7.25 - 7.32 (m, 1 H) 7.32 - 7.37 (m, 2 H) 7.37 - 7.45 (m. 3 H) 7.54 (s, 1 H).
Example 11-38: 1H NMR (400 MHz1 DMSO-d6) δ ppm 1.15 (t, J = 7.73 Hz, 3 H) 2.39 (d, J ~ 6.8 Hz, 2 H) 2.79 (d, J= 6.8 Hz, 2 H) 3.46 - 3.56 (m, 2 H) 3.91 - 4.01 (m, 2 H) 4,21 - 4.29 (m, 1 H) 7.14 - 7.17 (m, 1 H) 7.28 (d, J ~ 8.3 Hz, 2 H) 7.39 - 7.42 (m, 1 H) 7,48 (t, J = 7.83 Hz, 1 H) 7.61 - 7.64 (m, 3 H) 7.69 - 7.70 (m, 1 H) 7.84 (d, J « 8.4 Hz1 1 H) 12.23 (br s. 1 H).
Example 11-39: 1H NMR (400 MHz, Methanol-d4) δ ppm 2.39 - 2.56 (m, 6 H) 2.87 (A of ABX, Jab = 13.6 Hz1 Jax = 7.6 Hz. 1 H) 2.94 (B of ABX1 J8b = 13.6 Hz, Jbx = 6.1 Hz, 1 H) 4.43 - 4.50 (m, 1 H) 7.15 - 7.20 (m, 1 H) 7.31 - 7.35 (m, 3 H) 7.45 - 7.48 (m, 3 H).
Example 11-40: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.24-2.37 (m, 4H), 2.73 (dd, 1H1 J * 7.83, 13.4 Hz), 2.88 (dd, 1H, J = 7.33, 13.4 Hz), 3.93 (s, 1H), 4.26-4.36 (m, 1H). 5.35 (be, 1H), 7.33 (d, 2H, J = 8.08 Hz)1 7.38-7.43 (m, 1H), 7.48 (t. 1H, J = 7.83 Hz), 7.63 (d, 3H, J * 8.34 Hz), 7.70 (t, 1H, J « 2.02 Hz), 7.73 (d, 1H, J = 9.09 Hz)1 12,26 (bs, 2H).
Example 11-41 : 1H NMR (400 MHz, DMSO-d6) 6 ppm 2.21-2.33 (m, 4H)1 2.65-2.81 (rn, 2H)1 4.02 (d, 1H, J = 4.04 Hz). 4,24-4.32 (m, 1H), 5.56 (bs, 1H), 7.27 (d, 2H. J = 8.34 Hz), 7.37- 7.42 (m, 1H)1 7.47 (t, 1H1 J * 7.83 Hz)1 7.58 (d, 2H1 J * 8.34 Hz), 7.60-7.64 (m, 1H)1 7.69 (t, 1 H, J = 1.77 Hz). 7.96 (d. 1H, J = 8.84 Hz), 12.03 (bs, 1H), 12.60 (bs, 1H).
Example 11-42. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.22-2.37 (m, 4H), 2,74 (dd, 1H, J * 8.34, 13.4 Hz), 2.86 (dd, 1H, J = 6.82, 13.4 Hz), 3.34 (s, 3H), 3.62 (d, 1H1 J ~ 2.78 Hz), 4.34- 4.44 (m, 1H). 7.31 (d, 2H, J « 8.34 Hz), 7.38-7.43 (m. 1H), 7.48 (t, 1H, J * 7.83 Hz). 7.63 (d, 3H, J a 8.34 Hz), 7,71 (s, 1H)1 7.89 (d, 1H, J = 9,35 Hz).
Example 11-43: 1H NMR (400 MHz1 DMSO-d6) δ ppm 2.17-2.37 (m, 4H)1 2.64-2.81 (m, 2H), 3,37 (S, 3H), 3.77 (d, 1H1 J = 4.04 Hz), 4.25-4.34 (m, 1H)1 7.25 (d, 2H, J ~ 8.08 Hz), 7.38- 7.42 (m. 1H), 7.47 (t, 1H, J * 7.83 Hz), 7.56-7.64 (m, 3H). 7.68 (t, 1H, J = 1,77 Hz), 8.05 (d, 1H, J = 8.84 Hz), 12.05 (bs, 1H), 12.89 (bs, 1H).
Example 11-44: 1H NMR (400 MHz1 DMSO~d6) δ ppm 2.20-2.39 (m, 4H)1 2.65-2.87 (m, 2H)1 4.37-4.56 (m, 1H), 4.91 (d. 0.5H, J = 2.78 Hz), 5.04 (d, 0.5H, J = 3.03 Hz)1 7.29 (d, 2H, J ~ 8.34 Hz), 7.38-7.43 (m, 1H), 7.47 (t, 1H, J = 7.83 Hz), 7.58-7.65 (m, 3H), 7.69 (t, 1H, J = 1.77 Hz), 8.27 (d, 1H, J = 8.59 Hz), 12.05 (bs, 1H)1 13,57 (bs, 1H).
Example 11-45: 1H NMR (400 MHz, DMSOdβ) δ ppm 1.10 (d, J=7.1 Hz1 3 H), 2.17 - 2.37 (m, 4 H). 2,57 - 2.78 (m, 3 H), 4.19 - 4.31 (m, J-9.2, 9,2, 4.5, 4,3 Hz, 1 H), 7.30 (d, >8.1 Hz1 2 H)1 7.37 - 7.42 (m, 1 H), 7.47 (t, J=7.8 Hz, 1 H), 7.57 - 7.65 (m, 3 H), 7.70 (t, J»1.8 Hz, 1 H), 7,86 (d. J«8.8 Hz, 1 H), 12.21 (br. s., 2 H).
Example 11-46. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (dd, J-6.6, 3.5 Hz, 1 H), 2.82 (d, J=7.1 Hz, 1 H)1 3.88 (dd. ./«20.2, 15.2 Hz, 1 H), 4.03 (s, 1 H), 4.29 - 4.41 (m, 1 H)1 7.29 (d, J-8.3 Hz1 1 H), 7.37 - 7.43 (m, 1 H), 7.4$ (t. J~β.O Hz, 1 H), 7.62 (d, J=8,3 Hz, 2 H), 7.70 (t, J=1.8 Hz, 1 H), 7.89 (d. J-8.8 Hz, 1 H), 11 ,65 - 13,45 (m, 1 H). Example 11-47 /48: (R)>3-[{S)-2»(Carboxymetiiy!-amino)-propionylamino}-4-(3>-chloro« biphenyl-4-y()-butyric acid and (R)-3-((R)-2>(Carboxymethyl-amino)-propionylamino]-4- (3'-chloro-bϊphenyl-4-yl)«butyric acid
Figure imgf000193_0001
To a solution of (R)-3-[2-(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-propionylamino]~ 4-(3'-chloro-biphenyl-4-yl)-butyπc acid ethyl ester (290 mg, 0,504 mmol) in THF (3 ml) and MeOH (0.5 ml) at room temperature is added 2M NaOH (1.009 ml, 2.017 mmol). The reaction is stirred at room temperature over night. The mixture is concentrated to dryness and the crude i taken up in DCM (3.00 ml), to which is added TFA (3.89 ml, 50.4 mmol) and the mixture is stirred at room temperature for 2hr. The reaction is concentrated for HPLC purification. Reverse phase HPLC [25 to 50% ACN-H2O (0.1%TFA) over 10 min by Sunfire C18 column] give (R)-3-[(S)-2-(Carboxymethyl-amino)-propionylamino]-4-(3'-chloro-biphenyl- 4-y!)-butyric acid and (R)-3-[(R)-2-(Carboxymethyl-amino)-propionytamino]-4-(3'-ch!oro- biphenyl~4-yl)-butyric acid.
(R)-3-((S)-2-(Carboxymethyl-amino)-propionylamino]-4-(3'-ch!oro-biphenyl-4-yl)-butyric ack-: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, >7.1 Hz, 3 H)1 2.40 (dd, J«15.7, 8.3 Hz, 1 H)1
2.51 - 2.56 (m, 1 H), 2.76 (dd, J=13.4, 8.1 Hz1 1 H), 2.87 (dd, J«13.4, 5.3 Hz, 1 H), 3.43 -
3.52 (m, 3 H), 3.67 (q. J=67 Hz. 1 H)1 4.25 - 4.36 (m, 1 H), 7.30 (d, J=8.3 Hz1 2 H), 7.38 - 7.43 (m. 1 H), 7.48 (t, J=7.8 Hz, 1 H). 7.59 - 7.65 (m, 3 H), 7.70 (t, J*1.8 Hz1 1 H), 8.41 (d. J=8.3 Hz, 1 H). HRMS: Calcd for C21H23CIN2O8: 418.1295; found: m/z 418.1307, LCMS (condition A): 419 (M+1); retention time ~ 0,93 min; (R)-3-[(R)-2-(Carboxymethyl-amino)- propionylamino]-4-(3l-chtoro-biphenyl-4-yl)-butyric acid: 1H NMR (400 MHz1 DMSO-cfe) δ ppm 1.17 (d, J=6.8 Hz, 3 H), 2.41 - 2.49 (m, 0 H). 2.51 - 2.57 (m, 1 H)1 2.73 (dd, >13.4, 9.1 Hz, 1 H)1 2.91 (dd, J=13.4, 4.8 Hz1 1 H), 3.55 - 3.67 (m, 2 H), 3.67 - 3.74 (m, 1 H), 4.26 - 4.40 (m, 1 H)1 7.29 (d, J=8.3 Hz, 2 H), 7.39 - 7.44 (m, 0 H)1 7.48 (t, J=7.8 Hz. 0 H), 7.59 - 7.65 (m, 3 H)1 7.69 (t, J-1.8 Hz1 1 H), 8.43 (d, J-8.6 Hz1 1 H). HRMS: Calcd for C21H23CIN2O6: 418.1295; found: m/z 418.1305. LCMS (condition A): 419 (M+1); retention time ~ 0.99 min. Foilowing compounds are prepared using similar procedure as described in example 11- 47/48:
Figure imgf000194_0002
Example 11-49: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39 - 2.50 (m. 2 H) 2.77 - 2.89 (m, 2 H) 3.61 - 3.71 (m, 2 H) 3.81 (s, 2 H) 4.26 - 4.35 (m. 1 H) 7.31 (d, J ~ 8.3 HZ, 2 H) 7.40 - 7,43 (m, 1 H) 7.47 - 7.50 (m, 1 H) 7.62 - 7.65 (m, 3 H) 7.69 - 7.70 (m, 1 H) 8.49 (d, J ~ 7.3 Hz1 1 H).
Example 12-1: Synthesis of (/?)-4~(1-carboxy-3-(3'*chlorobipheny(-4~yl)propan-2- ylamino)~4-oxobutanoic acid
Figure imgf000194_0001
To a solution of (R)-4-(1~(2't5'-dichlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4- oxobutanoic acid (106 mg, 0.234 mmol) in THF (2 ml) and MeOH (0.1 ml), 1M aqueous NaOH solution (1.406 ml_, 1.406 mmol) is added at room temperature. After stirring for 4.5 hours, the reaction Is quenched with 0.1 M aqueous HCt (3 ml), and the products are extracted with EtOAc. The combined organic layer is washed with brine, dried over Na?Sθ4, filtered, and concentrated under reduced pressure. The crude is triturated in DCM. The precipitates are collected on a funnel, washed with DCM, and dried under reduced pressure to give {/:?)-4-(1-carboxy~3-(3'-chJorobiphenyl-4-yl)propan-2-ylamino)-4-o^ooutaπo'c acid (64.0 mg) as white solid; HPLC retention time « 1.24 minutes (condition A); MS (m+1) - 424.07; 1H NMR (400 MHz, CD3OD) δ ppm 2.38-2.42 (m, 2 H) 2.45 - 2.57 (m. 4 H) 2.87 (A Of ABX, Jab - 13.6 Hz, J8x = 7.6 Hz, 1 H) 2.95 (B of ABX, JΛ « 13.6 Hz, Λx = 6 1 Hz1 1 H) 4.44 - 4.51 (m, 1 H) 7.30 - 7.37 (m, 6 H) 7.47 (d. J = BA Hz, 1 H).
Example 13*1: Synthesis of (R)-4-(1-(biphβnyl-4-yl)-3-carboxypropan-2- ylcarbamoyl)picolinic acid
Example 13-2: Synthesis of (R)-2-(1-(biphenyl-4-yl)-3-carboxypropan-2- ylcarbamoyOisonicotinic acid
Figure imgf000195_0001
To a solution of (R)-ethyl 3-amino-4-(biphenyl-4-yl)butanoate hydrochloride (200 mg, 0.625 mmol), 2,4~pyridinedicarbσxy)ic acid hydrate (151 mg, 0.813 mmol), EDCI (132 mg, 0.688 mmol) and i-hydroxy-7-azabenzotriazole (94 mg, 0.688 mmol) in DMF (6 ml), DIPEA (0.164 ml, 0.938 mmol) is added. The reaction mixture is allowed to stir for 3 hours, Then, the reaction mixture is diluted with H2O. The precipitated solid is collected on a funnel and dried under reduced pressure. To a solution of the crude in THF (8 ml) and MeOH (1 mi), 1 M aqueous NaOH (2.5 ml, 2.5 mmol) is added. After stirring for 1 hour, the reaction is quenched with 5% citric acid and brine, and the products are extracted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1 % TFA) to 100% MeCN to give (R)-4-(1-(biphenyt-4-yl)-3-carboxypropan-2- ylcarbamoyl)pico!inic acid and (R)-2-(1-(biphenyl-4-yl)-3-carboxypropan-2- ylcarbamoyl)isonicotinic acid as white solids, respectively (Example 13-1: 33 mg; Example 13-2: 36 mg). Example 13-1 , HPLC retention time = 1,50 minutes (condition D); MS (m+1) » 405.1 ; 1H NMR (400 MHz, DMSO-d6) 6 ppm 2.53 - 2.62 (m, 2 H) 2.88 - 2.97 (m, 2 H) 4.50 - 4.59 (m, 1 H) 7.31 - 7.35 (m. 3 H) 7.42 - 7.45 (m, 2 H) 7.57 - 7.64 (m, 4 H) 7.89 (dd, J = 5, 1.6 Hz, 1 H) 8.83 (dd, J * 5, 0.8 Hz, 1 H) 8.37 (dd, J = 1.6, 0.8 Hz) 8.89 (d, J = 8.3 Hz1 1 H). Example 13-2, HPLC retention time - 1.24 minutes (condition A); MS (m+1) = 405.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 - 2.68 (m, 2 H) 2.91 (A of ABX, Jat> ~ 13.6 Hz, J8x = 6.1 Hz, 1 H) 3.01 (B of ABX, Jβb » 13.6 Hz, Jbx = 8.1 Hz, 1 H) 4.56 - 4.65 (m. 1 H) 7.29 - 7.34 (m, 3 H) 7.41 - 7.45 (m, 2 H) 7.55 - 7.64 (m, 4 H) 7.99 (dd, J ~ 5, 1.6 Hz1 1 H) 8.34 (dd, J = 1.6, 0.8 Hz, 1 H) 8.84 (dd, J « 5, 0.8 Hz, 1 H) 8.90 (d, J - 9.1 Hz, 1 H) 12.26 (br s, 1 H) 13.87 (br s, 1 H).
Following compounds are prepared using similar procedure as described in example 13-1 and 13-2:
Figure imgf000196_0001
Example 13-3: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.55 (d, J - 6.6 Hz1 2 H) 2.91 (A of ABX, Jβt> ~ 13.6 Hz, J3x * 6.3 Hz, 1 H) 2.96 (B of ABX, JaB = 13.6 Hz, J^ - 7.6 Hz, 1 H) 4.46 - 4.55 (m, 1 H) 6.86 (br s, 2 H) 7.02 (d, J ~ 4.8 Hz1 1 H) 7.28 - 7.36 (m, 3 H) 7,42 - 7.46 (m, 2 H) 7,58 - 7.65 (m, 4 H) 8.39 (d, J « 9.1 Hz, 1 H) 8.45 (d, J ~ 4.8 Hz, 1 H). Example 14-1: Synthesis of (R)-3>(3-Carboxymethyl-urθJdo)-4-(3'"Chlorθ"biphenyl-4-yl)- bυtyric acid
Figure imgf000197_0001
To a solution of Intermediate 16-1 (90 mg, 0.254 mmol) and ethyl isocyanatoacetate (39.4 mg. 0.305 mmoJ) in DMF (3 mL) is added pyridine (2.93 g, 37.1 mmol) and the mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is used directly in the next step.
Next, the above residue is dissolved in EtOH (1 ml) and 1N NaOH (3 mL, 3 mmol) is added. The mixture is stirred at room temperature for 2 hours then is acidified with 1 N HCI. The mixture is extracted with EtOAc and the organic phase is washed with water, brine then dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA). LyophHization of the proper fractions gives the title compound; HPLC Retention time 0.98 minutes (condition C). MS 391.3 (M+1); 1H NMR (400 MHz, DMSO-d6): δ ppm 2.34 (d, J=7.33 Hz, 2H). 2.79 (d, J=6.57 Hz. 2H), 3.67 (d, J=5.56 Hz, 2H), 4.04-4.12 (m, 1H), 6.15 (t, J-5.81 Hz, 1H), 6.23 (d, J=8.34 Hz, 1H), 7.28-7.30 (m, 2H)1 7.39-7.42 (m. 1H). 7.48 (t, J = 7.83 Hz, 1H), 7 62-7.65 (m, 3H)1 7.71 (t, J=1 ,77 Hz, 1H), 12.32 (s, br, 2H).
Exampie 15-1 : (R)^3'-Chtoro-biphenyl-4-yl)«3-{<2H4etrazGU^5<arbonyl)«aminol- butyric acid
Figure imgf000197_0002
To a suspension of the starting material in MeOH (5 mi) at room temperature is added NaOH (2mL, 6.00 mmol) and the mixture is stirred until the reaction was completed. The reaction mixture is acidified to pH <4 and purified by HPLC (15% to 60% acetonitrile-^O with
0.1%TFA) to give (R)-4-(31-chloro-biphenyl-4-yl)-3-[(2H-tetrazole-5-carbonyl)-amino]-butyric acid (80 mg).
HPLC retention time ~ 0.95 minutes (condition B); MS (m+1) - 386.1; 1H NMR (400 MHz, DMSO-de) d ppm 2.52 - 2.61 (m, 1 H)1 2.61 - 2.72 (m, 1 H), 2.84 - 2.99 (m, 2 H), 4.51 - 4.64 (m, 1 H), 7.31 (d. J«8.1 Hz1 2 H), 7.36 - 7.41 (m, 1 H)1 7.46 (t, J=7.8 Hz, 1 H). 7.61 (d, J=8.3 Hz, 3 H), 7.68 (t, J=1.9 Hz, 1 H), 9.31 (d, J=8.8 Hz1 1 H), 12.32 (br. s., 1 H).
Following compounds are prepared using similar procedure as described in example 15-1 :
Figure imgf000198_0001
Example 15-2 1H NMR (400 MHz, DMSO-dδ) d ppm 2 52 - 2.72 (m, 2 H), 2 86 - 3 00 (m, 2 H), 4 52 - 4 65 (m, 1 H)1 7.11 - 7 20 (m, 1 H), 7 31 (d J=8 1 Hz. 2 H)1 7.43 - 7 51 (m, 3 H), 7 61 (d, J=8 3 Hz1 2 H), 9 28 (d, J=B 8 Hz, 1 H), 12 29 (br s., 1 H)
Example 15-3 1H NMR (400 MHz, DMSCMJ6) δ ppm 2 52 - 2.60 (m, J=15.9, 5 8 Hz1 1 H), 2 67 (dd, J=15 9, 7 8 Hz, 1 H), 2.87 (dd, J-13.6, 5.8 Hz1 1 H)1 2 95 (dd, J=13 6, 8 3 Hz, 1 H), 3.73 (s, 3 H), 4 52 - 4.64 (m, 1 H), 7 00 (td, J-7 4, 1 1 Hz, 1 H), 7 08 (d, J~9 1 Hz1 1 H)1 7.22 - 7 27 (m. 3 H), 7 28 - 7 34 (m, 1 H), 7.37 (d, J~8 3 Hz1 2 H), 9 30 (d, J=8 8 Hz, 1 H), 12.28 (br s , 1 H)
Example 16*1 : N-[(R)'M3'-chtoro-foiplienyl<4«ylfnethyl)-3-meti)dnesulfonylamino4-oxo» propylj-succinamic acid
Figure imgf000199_0001
[(R)-1-(3l-Chloro-bιphenyt-4-ylmethyl)-3-methanesulfonyiamino-3-oxo-propyl]-carbamrc acid tørt-butyl ester (150 mg 0 321 mmol) is treated with 4M HCI in dioxane After being stirred at room temperature for 1h, the reaction mixture is concentrated m vacuo To this residue in DCM (2 mL) are added succinic anhydride (48.2 mg, 0 482 mmol) and tnethylamine (0 112 mL, 0 803 mmol) After being stirred at room temperature for 2h, the reaction mixture is diluted with EtOAc and washed with 1M HO and brine The organic layer is dried over Na2SO4 and cocentrated The residue is puπfiied by reverse phase HPLC (SunFire C 18, 0 1%TFA in H2O/CH3CN) to give N-[(R)«1-(3'-chloro-bιphenyl-4-yJmethyl)-3- methanesulfonylamιno-3-oxo-propy!}-succιnarnιc acid (63 mg) HPLC retentions time = 1 32 minutes (condition A), MS (m+1) = 467, 1H NMR (400 Mz1 DMSO-d6) δ ppm 2 22-2 29 (m, 2 H), 2 32-2 54 (m, 4 H), 2 77 (d, 2 H, J = 6 82 Hz)1 3 17 (s, 3 H), 4 31 (dt, 1 H, J = 7 33, 13 9 Hz), 7 28 (d, 2 H, J * 8.08 Hz), 7 38-7 43 (m, 1 H), 7 48 (t, 1 H, J « 7 83 Hz)1 7 62 (d, 3 H, J = 8 34 Hz), 7.70 (t, 1 H, J « 2 02 Hz), 7.89 (d, 1 H, J « 8.34 Hz), 11.70 (s, 1 H), 12 04 (s, 1 H).
Following compounds are prepared using similar procedure as described in example 16-1:
Figure imgf000200_0001
Figure imgf000201_0001
Example 16-2. 1H NMR (400 MHz, DMSO-Ct6) δ ppm 0.96 (t, 3 H1 J = 7.33 Hz), 1.66 (dd, 2 H, J = 7.33, 15.2 Hz), 2.25 (t, 2 H1 J = 7.07 Hz), 2.31-2.45 (m, 4 H), 2.76 (d, 2 H, J = 6.82 Hz), 3.25-3.32 (m, 2 H), 4.30 (dd, 1 H1 J = 7.83, 14.7 Hz). 7.28 (d, 2 H, J = 8.34 Hz)1 7.38-
7.43 (m, 1 H)1 7.48 (t, 1 H, J = 7.83 Hz), 7,63 (d, 3 H, J = 8.08 Hz), 7.70 (t, 1 H1 J ~ 1.77 Hz), 7.89 (d, 1 H, J = 8.34 Hz), 11,61 (S1 1 H), 12.04 (s, 1 H).
Example 16-3: 1H NMR (400 MHz, DMSO-dβ) δ ppm 2.24-2,31 (m, 2 H), 2.34-2.40 (m, 2 H),
2.44 (d, 2 H1 J- 6.82 Hz), 2.78 (d, 2 H1 J = 6.82 Hz), 4.26-4.36 (m, 1 H), 4.67 (s, 2 H)1 7.25- 7.33 (m, 4 H)1 7.34-7.43 (m, 4 H), 7.48 (t, 1 H1 J = 7.58 Hz)1 7.63 (d, 3 H, J = 8.34 Hz), 7.70 (t, 1 H, J = 1.77 Hz), 7.92 (d, 1 H, J = 8.34 Hz)1 11.60 (s, 1 H), 12.05 (s, 1 H).
Example 16-4: 1H NMR (400 MHz, DMSOd6) δ ppm 2.19-2,29 (m, 4H). 2.36 (dd, 2H, J = 6,57, 6.57 Hz), 2.72 (dd, 1 H1 J= 7.83, 13.6 Hz), 2.81 (dd, 1H, J = 5.31 , 13.6 Hz)1 4.17-4.27 (m, 1H), 6.83 (s, 1H), 7.28 (d, 3H, J * 8.34 Hz), 7.38-7.43 (m, 1H), 7.47 (t, 1H1 J = 7.83 Hz), 7.58-7,65 (m. 3H), 7.69 (t, 1 H. J = 1.77 Hz)1 7,78 (d, 1 H, J - 8.34 Hz)1 12.05 (S, 1H).
Example 16-5: Synthesis of N-C(R)-I -(3'-chloro-biphenyl-4-ytmethyl)-3- methanesulfonyIamino-3-oxo-propyl]-succinamic acid butyl ester
Figure imgf000202_0001
To a solution of N-[(R)-1-(3''Chloro-biphenyl-4-yfmethyl)'3-methanesulfonylamino-3-oxo- propylj-succinamic acid (50 mg, 0.107 mmol) in n-butanol (2 mL) is added thionyl chloride (9.38 μi, 0.128 mmol). The reaction mixture is warmed to 50 °C and stirred for 1 h. After cooling to room temperature, the reaction mixture is concentrated and purified by reverse phase HPLC (SunFire C18, 0.1%TFA in H2OZCH3CN) to give N-[(R)-1-(3'-chloro~biphenyl-4- ylmethyO-S-methanesutfonyiarninσ-S-oxo-propylJ-succinamic acid butyl ester (32 mg). HPLC retentions time ~ 1.56 minutes (condition A); MS (m+1) ~ 523; 1H NMR (400 Mz, DMSO-d6) δ ppm 0.86 (t, 3H, J - 7.33 Hz), 1.22-1.34 (m, 2H), 1.45-1.55 (m, 2H)1 2.23-2.33 (m, 2H), 2,35-2.44 (m, 3H), 2,45-2.55 (m, 3H), 2.71-2.83 (m, 1H), 3.18 (s, 3H)1 3.96 (t, 2H, J ~ 6.57 Hz), 4.27-4.38 (m, 1H), 7.28 (d, 2H, J ~ 8.08 Hz), 7.37-7.43 (m, 1H), 7.48 (t, 1H J = 7.83 Hz), 7,62 (d, 3H, J- 8.34 Hz), 7.70 (s, 1H), 7.91 (d, 1H, J ~ 8.34 Hz), 11.71 (s, 1H).
Example 17: (R)~3-(2-acetyloxazole-5-carboxamidoH-(3'-chlorobiphenyl-4-yl)butanoic acid
Figure imgf000202_0002
To a solution of (R)-4-(3'-chlorobipheny!-4-yt)-3-(2-(prop-1-en-2-yl)oxazole-5- carboxamido)butanoic acid (60 mg, 0.14 mmol) in DCM (2 rr»L) and MeOH (2 mL) at -78°C is bubbled ozone for 30 seconds. After 30 seconds ozone is removed and oxygen is bubbled for 10 minutes. After bubbling oxygen for 10 minutes the -78°C bath is removed and the reaction is quenched with polymer supported triphenylphosphine and the reaction is stirred at room temperature for 2 hours. After 2 hours the reaction is filtered to remove triphenylphosphineoxide on supported polymer and the filtrate is collected and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C 18, H2O(0.1% TFA)/CH3CN). and then lyophilized to give (R)-3-(2-acetyloxazole-5- carboxamtdo)-4-(3'-chlorobiphenyl-4-yl)butanoic aαd (13 mg). HPLC retention time « 1.67 minutes (condition D); MS (m+1) - 427.0; 1H NMR (400 MHz, DMSO-Cf6) δ ppm 2,53 - 2.59 (m, 2 H) 2.60 (s, 3 H) 2.87 (dd, ./=10.9, 3.3 Hz, 1 H) 2.94 (dd, J=10.9, 5.1 Hz, 1 H) 4.46 - 4.60 (m, 1 H) 7.31 (d, J=8.1 Hz, 2 H) 7.36 - 7.43 (m, 1 H) 7.47 (t, J=7.8 Hz, 1 H) 7.62 (d, J=8.3 Hz, 3 H) 7.69 (t, J=1.9 Hz, 1 H) 7 94 (s, 1 H) 8.86 (d, J-B.6 Hz, 1 H) 12.31 <br. β., 1 H).
Starting materials or intermediates are prepared in following manner:
Intermediate 1 : (R)-ethyl 4-(4-bromophenyl)-3-(4-methoxy-4>oxobutanamido)butanoate
Figure imgf000203_0001
To (R)-ethyl-4-(4-bromophenyl-4-yl)-3-(fert-butoxycarbonylamino)butanoate (2.02 g, 5.23 mmol) is added a solution of 4M HCI in 1,4-dioxane (13.1 mL, 52.3 mmol) at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to give (R)-3-amino~4-brornophenyl^-yl-butyric acid ethyl ester hydrochloride. To a solution of (ft)-3-amino-4-bromophenyl-4-yl-butyric acid ethyl ester hydrochloride is added succinic anhydride (0.707 g, 7.06 mmol) and DIPEA (2.06 mL. 11.8 mmol) in dichloromethane (20 mL) and allowed to stir for 4 hours. The reaction is quenched with 0.1 M aqueous HCI. The products are extracted with ethyl acetate and washed with brine. The organic layer is dried over Na2sO4, filtered, and concentrated under reduced pressure to give (R)-4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (2.26 g), To a solution of the obtained residue (2.26 g) in toluene (25 mL) and MeOH (25 mL), TMSCHN2 in hexanes (5.85 mi, 11.70 mmol) is added portionwise at room temperature under nitrogen. The reaction mixture is allowed to stir for 1.5 hour, then quenched with AcOH (0.5 mL; 8.78 mmol), and the solution is stirred for 10 minutes. The solution is concentrated, and the obtained residue is purified by flash column chromatography on 40 g silica gel (eluent: heptane/EtOAc = 100:0 to 0:100) to give (R)-ethyl 4-(4-bromophenyl)-3-(4- methoxy-4-oxobutanamido)butanoate (1.92 g). HPLC retention time = 1.04 minutes {condition B); MS (ES+) = 400 (m+1), 402.0 (m+3; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J-12 Hz, 3 H) 2.40 - 2.53 (m, 4 H) 2.60 - 2.64 (m, 2 H) 2.79 (A of ABX, Jab - 13.7 Hz. Jax » 7.85 Hz, 1 H) 2.90 (B of ABX, Jab = 13.7 Hz1 Jbx = 6.65 Hz1 1 H) 3.68 (s, 3 H) 4.10 - 4.22 (m, 2 H) 4.39 - 4.47 (m, 1 H) 6.29 (br d, J - 8.6 Hz, 1 H) 7.06 (d, J s 8.4 Hz, 2 H) 7.40 - 7.42 (m, 2 H).
Intermediate 2: (ft)-ethyl 4~(biphenyJ-4-yl)-3-(tert-butoxycarbonylam3no)butanoate
Figure imgf000204_0001
A mixture of (RJ-elhyl 4-(4-bromophenyl)-3~(tert-butoxycarboπylamino)butanoate (1.5 g, 3.88 mmol), phenylboronic acid (0.710 g, 5.82 mmol), Pd(Ph3P)4 (0.449 g, 0.388 mmol) and aqueous Na2CO3 (3.88 ml, 7.77 mmol) in toluene (25 mL) is allowed to stir at 95 °C under nitrogen for 14 hours. The reaction mixture is cooled to room temperature and quenched with brine. The mixture is extracted twice with ethylacetate, and the combined organic layer is washed with brine, dried over Na?SO4l filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc « 100:0 to 50:50) to give (ft^ethyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (1.30 g): HPLC retention time = 1.61 minutes (condition 8); MS (ES+) = 328.0 (m-tBu+2); 284.1 (m-Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-rf) δ ppm 1.28 (t, J - 7.1 Hz, 3 H) 2.48 (A of ABX, Jab ~ 16.1 Hz, Jax ~ 5.9 Hz, 1 H) 2.53 (B of ABX, Jab « 16.0 Hz. Jbx - 5.3 Hz1 1 H) 2.83 - 3.00 (m, 2 H) 4.14 ~ 4.19 (m, 3 H) 5.06 (br s) 7.26 - 7.27 (m, 2 H) 7.31- 7.35 (m, 2 H) 7.43 (t, J * 7.6 Hz, 2H) 7.52 -7.58 (m, 4 H). Follσwing intermediates are prepared using similar procedure as described for intermediate 2:
Figure imgf000205_0001
Figure imgf000206_0002
intermediate 3: (R)<4-(1 -(bιphenyl-4-yl)-4-tert-butoxy-4~oxøbutan~2-ylamino)-4- oxobutanojc acid
Figure imgf000206_0001
To (f?)-tert-bυtyl 4-(bipheny{-4-y{)'3-(tert-butoxycarbonyiamino)butanoate (26.4 mg, 0.064 mmol) is added 4M HCI in 1 ,4-dioxane (0.321 ml, 1.283 mmol) at room temperature. The reaction mixture is stirred for 45 minutes and concentrated under reduced pressure. To a solution of the obtained residue in dichloromethane (0.4 mL) is added succinic anhydride (7.70 mg, 0.077 mmol) and DIPEA (0.013 mL, 0.077 mmol). The reaction mixture is allowed to stir at room temperature for 14 hours and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C-18, H2O(0.1%TFA)/CH3CN) to give (R)- 4-(1-(biphenyl-4-yl)-4-tert-butoxy-4-oxobutan-2-yiamino)-4-oxobutanotc acid (9.5 mg). HPLC retention time « 1.70 minutes (condition A); MS (ES+) = 412.1 (m+1); 356.0 (m-tBu+2; 100%); 1H NMR (400 MHz1 CHLOROFORM-tf) δ ppm 1.48 (s, 9 H) 2.36 -2.51 (m, 4 H) 2.64 - 2.67 (m, 2 H) 2.87 (A of ABX, Jab = 13.5 Hz. Jax » 5.7 Hz, 1 H), 2.97 (Jab = 13.5 Hz, Jbx = 6.2 Hz, 1 H) 7.24-7.26 (m, 2 H) 7.31-7.35 (m, 1 H) 7.43 (t, J » 7.75 Hz, 2 H) 7.53(d, J = 8.0 Hz1 2 H) 7.57 (d, J ~ 7.6 HZ, 2 H). Following intermediates are prepared using similar procedure as described in intermediate 3:
Figure imgf000207_0002
Intermediate 4: (R)-tert-butyl 4-(biphenyi-4-yl)-3-(tert-butoxycarbonylamino)butanoate
Figure imgf000207_0001
A solution of (R)-2-(biphenyl-4-yfmethyl)-4-tert-butoxy-4-oxobutanoic acid (100 mg, 0.294 mmol), DPPA (0.076 mL, 0.353 mmol) and Et3N (0.049 mL, 0.353 mmol) in Toluene (1.5 mL) is allowed to stir at 100 °C under nitrogen for 2 hours. tBuOH (0.281 mi, 2.94 mmol) is added and the mixture is refluxed for 5 hours at the same temperature. The reaction is cooled to room temperature, and the solvent is removed. Ethyl acetate is added to the obtained residue, and the organic layer is washed with 5% aqueous citric acid, H3O, satυrated aqueous NaHCO3. and brine. The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on 40 g of silica gel (heptane/EtOAc = 100:0 to 50:50) to give the corresponding isocyanate (35.7 mg). The obtained isocyanate is dissolved in tBuOH (0.3 mL) and the solution is allowed to stir at 80 °C for 20 hours. The reaction mixture is concentrated, and the residue is purified by flash column chromatography on 12 g of silica gel (heptane/εtOAc * 100:0 to 70:30) to give (R)-tert-butyl 4~(biphenyl-4-yl)-3«(tert- butoxycarbonylamino)butanoate (26.4 mg, 22%), HPLC retention time - 1.74 minutes (condition B); MS (ES+) = 356.0 (m-tBu+2) 300.0 (m-tBux2+3; 100%); 1H NMR (400 MHz1 CHLOROFORM-c/) δ ppm 1.41 (s, 9 H) 1.47 (s, 9 H) 2.36 (A of ABX, Jab « 15.6 Hz, Jax = 6.2 Hz. 1 H) 2.44 (B of ABX, Jab = 15.5 Hz1 Jbx = 5.45 Hz) 2.82 - 2.97 (m, 2 H) 4.15 (br s) 5.09 (br d) 7,6-7.35 (m, 3H) 7.41 - 7.45 (m, 2 H) 7.51-7.56 (m, 4 H).
Intermediate 5: (R)-ethyl 4-(4-bromophenyi)-3-(tert-butoxycarbonyfamino)butanoate
Figure imgf000208_0001
To a suspension of (R)-4-(4~brornophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (9.98 g, 27,9 mmoi) and NaHCO3 (4.68 g, 55.7 mmol) in OMF (45 mL) is added Ethyl iodide (6.75 mL, 84 mmol) at room temperature under nitrogen. After stirring for 71 hours, the reaction is quenched with H2O (300 mL), and then precipitated solid is collected and washed with H2O (500 mL) to give (R)-ethyl 4-(4-bromophenyl)-3~(tert-butoxycarbonylamino)butanoate (10.25 g, 94%). HPLC retention time « 1.48 minutes (condition B); MS (ES+) = 329.9 (m-tBu+2); 286,0 (m-Boc+2; 100%); 1H NMR (400 MHz1 CHLOROFORM-cQ δ ppm 1.27 (t, J = 7.2 Hz, 3 H) 1.40 (S1 9 H)1 2.43 (A Of ABX1 Jab « 15.8 Hz, Jax * 5.7 Hz1 1 H) 2.50 (B of ABX, Jab = 15.8 Hz, Jbx - 5.4 Hz, 1 H) 2.74 - 2.90 (m, 2 H) 4.11 (br 8) 4.15 (q, J = 7.1 Hz, 2 H) 5,04 (br d) 7,07 (d, J = 8.3 Hz1 2 H) 7.40-7.43 (m, 2 H).
Following intermediates are prepared using similar procedure as described for intermediate 5: -
Figure imgf000208_0002
, ____. „ , . „
Figure imgf000209_0001
Figure imgf000210_0002
intermediate 5-2: (R)-benzyt 4'(4-toromopKenyl)-3-(tert- butoxycarbonylaminojbutanoate
Figure imgf000210_0001
To a suspension of (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylam'rno)bυtanoic acid (5.02 g, 14.01 mmol) and NaHCO3 (3.53 g, 42.0 mmol) in DMF (20 mL) is added Benzyl bromide (5.10 mL, 42 mmol) at room temperature under nitrogen. After stirring for 46 hours, the reaction is diluted with H2O (200 mL), and then precipitated solid is collected and washed with H2O (500 mL) and then with heptane (200 mi) to give (R)-benzyl 4-(4-bromophenyl)-3- (tert-butoxycarbonylamino)butanoate (5.61 g, 89%). HPLC retention time » 1.56 minutes (condition B); MS (ES+) * 392.1 (m-tBυ+2); 348.1 (m«Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 9 H) 2.48 (A of ABX, Jab ~ 15.9 Hz, Jax ~ 5.6 Hz, 1 H) 2.54 (B Of ABX1 Jab - 15.9 Hz, Jbx = 5.3 Hz, 1 H) 2.72 - 2.88 (m, 2 H) 4,11 (br s, 1 H) 5.02 (br s, 1 H) 5.10 (A of AB, J = 12.1 Hz, 1 H) 5,16 (A of AB1 J = 12.1 Hz, 1 H) 7.00 (d, J * 8.1 Hz1 2 H) 7.34-7.39 (m, 7 H).
Intermediate 6: (R)-3-(biphenyi-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4- oκobutanoic acid
Figure imgf000211_0001
To a solution of (R)-tert-butyl 3-(biphenyl-4-y)methyl)-4-(3-methoxy-3-oxopropytamino)-4- oxobutanoate (40 mg, 0.094 mmol) in DCM (0.5 ml), TFA (0.15 ml) is added at room temperature. The mixture is allowed to stir for 2 hours, and then concentrated under reduced pressure to give (R)-3-{biphenyl-4-yimethy))-4-(3-methoxy-3-oxopropylaminσ)-4~oxobutanoic acid (33.5 mg, 96%). HPLC retention time - 1.20 minutes (condition A); MS (m+1) « 370.1 ; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.21 - 2.29 (m, 1 H) 2.38 - 2.45 (m, 1 H) 2.62 ~ 2.66 (m, 1 H) 2.75 - 3.00 (m ,4 H) 3,29 - 3.37 (m, 1 H) 3.45 - 3.53 (m, 4 H) 6.12 (br s, 1 H) 7.23 (d, J * 8 Hz. 2 H) 7.32 - 7.35 (m, 1 H) 7.41 -7.45 (m, 2 H) 7.53 (d, J « 8.1 Hz, 2 H) 7.56 ~ 7.59 (m, 2 H).
Intermediate 7: (R)-tert-butyl 3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3Oxopropylamino)« 4-oxobutanoate
Figure imgf000211_0002
A solution of (R)-2-(biphenyl-4-yimethyl)-4-tert-butoxy~4-oxobutanoic acid (142 mg, 0.417 mmol), 3-amino-propionic acid methyl ester hydrochloride (76 mg, 0.542 mmol), WSC hydrochJoride (120 mg( 0.626 mmol), 1-hydroxy-7-azabenzotriazoie (85 mg, 0.626 mmol) and DIPEA (0.219 ml, 1.251 mmol) in DMF (4 mL) is allowed to stir at room temperature under nitrogen for 13 hours. The reaction is quenched with H2O. The products are extracted with ethyl acetate, washed with aqueous 1M HCI and then with brine, dried over Na2SO,*, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on 12 g of silica gel (heptane/EtOAc = 70:30 to 0:100) to give (R)- tert-bυtyl 3'(biphenyl-4-ylmethyl)-4>(3-methoxy-3-oxopropylamino)-4-oxobutanoate (164 mg, 91%). HPLC retention time = 1.59 minutes (condition A); MS (ES+) « 425.4 (m); 369.4 (m- tBu+1; 100%); 1H NMR (400 MHz, CHLOROFORM-cf) δ ppm 2.24 - 2.44 (m, 2 H) 2.67 - 2.79 (m, 3 H) 2.89 -2.96 (m, 1 H) 3.28 - 3.36 (m, 1 H) 3.45 ~ 3.53 (m, 1 H) 7.23 (d, J = 5.8 Hz, 2 H) 7.33 (t, J = 7.35 Hz, 1 H) 7.41 - 7.44 (m, 2 H) 7.51 (d, J = 8.1 Hz, 2 H) 7.58 (d, J = 7.4 Hz, 2 H). Following intermediates are prepared using similar procedure as described in intermediate 7:
Figure imgf000212_0001
Figure imgf000213_0002
Intermediate 8: (R)-3*£(1 -benzyl-1 H-tetrazoJe-5-carbonyl>-aιτιino3-44>lphenyl-4'ylΦutyric acid ethyl ester and (R)'3-[(2~benxyl-2H-tetrazole-5-carbonyl)-amino]-4-biphenyl-4-yl* butyric acid ethyl ester
Figure imgf000213_0001
(R)-ethyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (117 mg, 0.305 mmol) is treated with 4M HCt dioxane solution (2 mL). After stirring for 0.5 hour, the reaction mixture is concentrated under reduced pressure. To a solution of the obtained residue and Et3ISJ (0.106 mL, 0.763 mmol) in DCM (3 mL) is added benzyi-W-tetrazoie-5-carbonyl chloride (mixture of 1 and 2-benzyl isomers, 82 mg, 0.366 mmol, prepared according to J.MedChem. 1986, 29, 538-549). After stirring for 10 minutes, Et3N (0.106 mL, 0.763 mmoJ) and the acid chloride (82 mg, 0.366 mmol) are added. After stirring for 0.5 hour, the reaction mixture is diluted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give (R)-3-{(1-benzyl-1H-tetrazoie-5-carbonyO-amino]-4-biphenyl-4-yt-butyric acid ethyl ester and (R)-3-((2-benzyl-2H-tetrazole-5-carbonyl)-amino]-4-biphenyl-4-yl-butyric acid ethyl ester. HPLC retention time = 1.51 minutes (condition D); MS * 470.0 (m+1); 1H NMR (400 MHz, CDCI3) 6 ppm 1.27 (t, J=7.07, 7.07Hz, 3H)1 2.57-2.70 (m, 2H), 3.00 (dd, J=7.58, 13.77Hz, 1H), 3.12 (dd, J=6.57, 13.77Hz, 1H)1 4.12-4.23 (m, 2H)1 4.71-4.80 (m, 1H), 5.80 (s, 2H)1 7.27-7.45 (m, 9H), 7.52 (d, J=8.34Hz. 2H), 7.56 (d, J=8.46Hz, 2H), 7.75 (d, J=7,33Hz, 1H). Jntβrmediate 9: (R)-4-biphenyl-4-yl-3-{3-[1 -(2-cyano-ethyl)-1 H-tetrazol-5-ylJ> propionylamino}-butyr»c acid ethyl ester
Figure imgf000214_0001
To a solution of (R)-4-biphenyi-4'yl-3-tert-bυtoxycarbonytamino-butyric acid ethyl ester (400 mg, 1.04 mmol) in DCM (10 mL) at room temperature is added TFA (2.009 ml, 26.1 mmol) and the mixture is stirred at room temperature for 1 hour. The mixture is concentrated under reduced pressure. To the obtained TFA salt in DCM (10 mL) at ice bath temperature is added succinic anhydride (125 mg, 1.25 mmol) and followed by TEA (0.363 mL, 2.61 mmol). The reaction is stirred at room temperature for 16 hours, The mixture is concentrated under reduced pressure. The obtained residue is purified by flash chromatography {silica gel, 2% to 5% EtOH/DCM) give (R)-4-biphenyl-4-yl-3-(3-carboxy-propionylamino)~butyric acid ethyl ester (200 mg). HPLC retention time = 1.53 minutes (condition C); MS « 384 (m+1).
Next, to a solution of (R)-4-btphenyl-4~yl-3-(3-carboxy-propionylamino)-butyric acid ethyl ester (200 mg, 0.522 mmol) in THF (10 mL) at room temperature is added EDC HCI (120 mg, 0.626 mmol) and HOBT (96 mg, 0.626 mmol). The reaction is stirred at room temperature for 10 minutes then added 3-aminopropionitrile (0.046 ml, 0.626 mmol) and TEA (0.087 ml, 0,626 mmol). After 1 hour, 0.5 equivalent of EDC HCI, HOBT, and 3~ aminopropionitrile are added and stirred for 16 hours. The reaction mixture is quenched by brine and is extracted with ethylacetate. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue is purified by flash chromatography (silica gel, 2% to 5% EtOH/DCM) to give (R)-4-biphenyl-4-yl-3-{3-(2-cyano-ethylcarbamoyl)-propionylamino}-butyric acid ethyl ester (218 mg. 96% yield). HPLC retention time = 0.77 minutes (condition E); MS = 436 (m+1).
Next, to a solution of (R)~4-biphenyl-4-yl-3-[3-(2-cyano-ethylcarbamoyl)-propionylamino]~ butyric acid ethyl ester (204 mg, 0.468 mmol) in THF (10 mL) at room temperature is added Ph3P (307 mg, 1.17 mmol) and the mixture is stirred at room temperature for 10 minutes. Then to the mixture at ice bath temperature is added OtAD (0.228 ml, 1.171 mmol) and trimethylsify! azide (0,155 ml, 1.171 mmof). The resulting mixture is slowly warmed up to room temperature and stirred for 16 hours. The reaction mixture is concentrated under reduced pressure. The obtained residue is purified by flash chromatography (silica gel, 1% to 3% EtOH/DCM) to give (R)-4-biphenyl-4-yl-3-{3-[1-(2-cyano-ethyl)-1H-tetra2ol-5-yl3- propionylamino}-butyric acid ethyl ester (137 mg, 64% yield). HPLC retention time = 1.61 minutes (condition C); MS « 461 (m+1).
Intermediate 10: (R)-2-(biphenyl-4-y1methyl)-4-tert-butoxy-4-oxobutanoic acid
Figure imgf000215_0001
O
To a stirred solution of (R)-tert-butyl 4-((S)-4-benzyl~2-oxooxazolidin-3-yl)-3-(bipheny!-4- ylmethyl)-4-oxobutanoate (1.20 g, 2.402 mmol) in a mixed solvent of THF (20 mL) and water (5 mL), a solution of aqueous H2O2 (0.960 mL, 9.61 mmol) and aqueous LiOH (4.80 ml, 4.80 mmol) is added at 0 °C during 5 minutes. After stirring for 15 hour, the reaction is quenched with saturated aqueous Na2SO3 (10 mL) at 0 °C, and allowed to stir for 10 minutes at the same temperature. The reaction mixture is warmed up to ambient temperature while stirring for 0.5 hour. Then, saturated aqueous NaHCO3 and brine are added to the mixture. The product is extracted with ethyl acetate, washed with aqueous 1M HCI, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on 120 g of silica gel (heptane/EtOAc « 75.25 to 0:100) to give (R)- 2-(biphenyl-4-yimethyl)-4-tert-butoxy-4-oxobutanoic acid (765 mg, 93%). HPLC retention time = 1.63 minutes (condition D); MS « 338.6 (m-1); 1H NMR (400 MHz, CHLOROFORM-cQ δ ppm 1.43 (s, 9 H) 2.41 (A of ABX, J** 16.67 Hz1 Jax - 4.55 Hz, 1 H) 2.52 - 2.67 (B of ABX, Jab a 16.75 Hz, Jbx = 8.45 Hz, 1 H) 2.74 - 2.89 (m, 1 H) 3.06 - 3.22 (m, 2 H) 7.22 - 7.29 (m, 2 H) 7.30 - 7.37 (m. 1 H) 7.43 (t, J=7.58 Hz, 2 H) 7.53 (d, J= 8.1 Hz, 2 H) 7.57 (d. J * 7.8 Hz, 2 H). intermediate 11 : Synthesis of (R)-tert-bυtyl 4-{(S)-4«benzyl-2-oxooxa2olidin-3-yl)~3- {biphenyl-4-ylmethyl)-4-αxobutanoate
Figure imgf000216_0001
A stirred solution of (S)~4-benzy)-3-(3-(biphenyl~4-yl)propanoyi)oxazolidin»2-one (intermediate 12: 5.01 g, 13.00 mmo!) in THF (180 mL) is cooled to -73.8 0C, and 1M THF solution of sodium hexamethyldisilylamide (14.30 ml, 14.30 mmol) is added during 5 minutes. After 30 minutes, a solution of tert-butyl bromoacetate (2.495 mL, 16.90 mmol) in THF (20 mL) is added dropwise during 5 minutes. The solution is stirred at -74 0C for 1 hour, and the reaction is quenched with saturated aqueous NH4CI (100 mL), and warmed up to ambient temperature. The precipitated solid is filtered off and washed with ethyl acetate (50 mL). The organic phase is separated, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The obtained residue is suspended in WIeOH (70 mL) and then filtered to collect the solid (5.9 g) as a mixture of the desired product and the starting material. The mixture is purified by flash column chromatography on 120 g of silica ge! (heptane/EtOAc ~ 90:10 to 50:50) to give (R)-tert-butyl 4-((S)-4-benzyi-2-oxooxazolidin- 3-yl)-3-(biphenyl-4-ylmethyl)-4~oxobutanoate (2.40 g, 37%). HPLC retention time = 1.74 minutes (condition B); MS - 499.4 (m+); 443.4 (m-t8u+1; 100%); 1H NMR (400 MHz1 CHLOROFORM-d) δ ppm 1.41 (s, 9 H) 2.42 (dd, J=16.67, 4.04 Hz, 1 H) 2.71 (ddd, J«16.55, 13.26, 9.60 Hz, 2 H) 2,87 (ddt J=16.93, 10.86 Hz1 1 H) 3.04 (dd, J=13.14, 6.32 Hz, 1 H) 3.32 (dd, J=13.39, 3.03 Hz, 1 H) 3.92 (t, J*8.34 Hz, 1 H) 4.07 (dd, J-8.97, 2.15 Hz1 1 H) 4.48 - 4.58 (m, 2 H) 7.20 - 7.30 (m, 3 H) 7.30 - 7.36 (m, 5 H) 7.42 (t, J=7.58 Hz, 2 H) 7.52 (d, J « 8.1 Hz, 2 H) 7.56 (d, J * 7.8 Hz, 2 H).
Intermediate 12: (S)-4-benzy!-3>{3-(biphenyl-4-yl)propanoyl)oxazoiidin-2-one
Figure imgf000217_0001
To a 1.6 M solution of n-Buϋ in hexane (12.1 mL, 19.3 mmol) is added dropwise a solution of ($)-(-)-4-benzyi-2-oxazolfdinone (3.26 g, 18.4 mmol) in dry THF (80 mL) at -71.6 °C under nitrogen over 10 minutes. The solution is warmed up to -60.5 °C while the addition, and allowed to stir for 1 hour in dry ice/MeOH bath. 3-(Biphenyl-4-yl)propanoyl chloride (intermediate 13: 5,46 g, 22.31 mmol) in dry THF (20 mL) is added dropwise at -72 °C over 5 minutes. The solution is warmed up to -56.5 °C while the addition. After stirring 10 minutes at the same temperature, the reaction mixture is allowed to warm to room temperature and stirring is continued for 3 hours. The reaction mixture is filtered, and the collected precipitate is washed with 20 mL (10 mL x2) of MeOH and then with 150 mL of H2O to give the desired product (4.26 g). The products in the mother liquor is extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is suspended in 80 mL of MeOH, and the suspension is filtered and washed with 20 mL of MeOH (1.79 g). The two fractions are mixed to give (S)-4-benzyl-3~{3- (biphenyi-4-yf)propanoy{)oxazolidin-2-one (6.05 g, 85% in 2 steps). Retention time = 1.77 minutes (condition A); MS (m-t-1) = 387.3; 1H NMR (400 MHz, CHLOROFORM-cO δ ppm 2.77 (dd, J-13.39, 9.35 Hz, 1 H) 2.99 - 3.15 (m, 2 H) 3.20 - 3.43 (m, 3 H) 4.09 - 4.24 (m, 2 H), 4.68 (dddd, ./«9.76, 6.73, 3.47, 3.28 Hz, 1 H) 7.18 (d. J-7,07 Hz, 2 H) 7.23 - 7.37 (m, 6 H) 7.42 (t, J-7.58 Hz, 2 H) 7.53 (d. J = 8.1 Hz, 2 H)1 7.57 (d, J * 7.8 Hz, 2 H).
Intermediate 13: 3-(biphenyl-4-yl)propanoyl chloride
Figure imgf000217_0002
A mixture of 3-(4-biphenylyl)propionic acid (5 g, 22.10 mmol) and SOCI2 (4.03 ml, 55.2 mmol) is refluxed under nitrogen at 85 °C for 1.5 hour, The reaction mixture is concentrated under reduced pressure to give 3-(biphenyl-4-y!)propanoyl chloride (5.46 g). The material is used in the next step without further purification.
Intermediate 14: (2R,4R)-4~Amino-2-methyl-pentanoic acid ethyl ester trifluoroacetate
Figure imgf000218_0001
To a stirred solution of 2-{triphenylphosphanylidene)-propionic acid ethyl ester (3.11 g, 8.57 mmol) in methylene chloride (20 mL) is added a solution of 3,3-dimethyl-N-((R)-1-methyl-2- oxo-ethyl)-butyramide (J. Med. Chem. 41 , 6 (1998) (135 g, 779 mmol) in methylene chloride (20 mL) and the mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is purified by column chromatography using a gradient of 10-50% heptane/EtOAc to give (E)-(R)-4-tert-butoxycarbonylamino-2- methyl-ρent-2-enoic acid ethyl ester. 1H-NMR (400 MHz, CDCI3); δ ppm 1.22 (d, J=6.44 Hz, 3H), 1.30 (t, 3H), 1.43 (s, 9H), 1.91 (s, 3H)1 4.19 (q, 2H), 6.51 (d, broad, J=7.45 Hz, 1H).
Next, a solution of (E)-(R)-4-tert-butoxycarbonylamino-2-methyl-pent-2-enoic acid ethyl ester (1.83 g, 7.11 mmol) In ethyl acetate (75 mL) is hydrogenated over 10% Pt/C (183 mg) at 1 atm for 18 hours. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by chiral HPLC to afford (2R,4R)-4-tert- butoxycarbonylamino-2-methyl-pentanoic acid ethyl ester, 1H-NMR (400 MHz, CDCi3); δ ppm 1.13 (t, 3H), 1.18 (m, 3H), 1.26 (t, 3H), 1.43 (s. 9H)1 1.81 (s, 1H)1 2.50 (m, 1H), 3.72 (m broad, 1H)1 4.14 (m, 2H), 4.33 (m broad, 1H).
Next, (2R,4R)-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid ethyl ester (142 mg, 0,548 mmol) is added to trifluonoacetic acid (5 mL). After 10 minutes, the solvent is removed under reduced pressure. Methylene chloride is added and the solvent is removed under reduced pressure to give (2R,4R)-4-amino~2-methyl-pentanoic acid ethyl ester trifluoroacetate. This material is used directly in the subsequent coupling reaction.
intermediate 15; 2-Biphenyl-4-ylmethyl-succinic acid 1 -methyl ester
Figure imgf000219_0001
To a solution of (triphenylphosphanyltdene)-acetic acid methyl ester (2.26 g, 6,77 mmol) in methylene chloride {25 mL) is added t-buty{ bromoacetate (1.32 g, 6.77 mmol) and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure and the residue is purified by column chromatography using a gradient of 80-100% heptane/EtOAc to afford 2-{triphenylphosphanylidene)-succinic acid 4-tert-butyl ester 1- methyl ester. MS 449.3 (M+1),
Next, a mixture of 2-(triphenylphosphanylidene)-succin»c acid 4-tert-butyl ester 1 -methyl ester (700 mg, 1.561 mmol) and biphenyl-4-carboxaldehyde (278 mg, 1.419 mmol) in toluene (20 mL) is refluxed for 4 days. The solvent is removed under reduced pressure and the residue is purified by column chromatography using a gradient of 0-30% heptane/EtOAc to give 2-t1-btphenyi-4-yl-meth-(Z)~yiidenej'Sυccintc acid 4-tert-butyl ester 1 -methyl ester as an oϋ, 1H-NMR (400 MHz. CDCI3); δ ppm 1.47 (s, 9H), 3.52 (s, 2H), 3.84 (S1 3H), 7.37 (t, 1H), 7.46 (t, 4H), 7.62 (t, 4H), 7.89 (β, 1H).
A solution of 2-[1-biphenyl-4-yl-meth-(Z)-y{idene]~succinic acid 4-tert-butyl ester 1 -methyl ester (410 mg, 1, 163 mmol) in ethy! acetate (20 mL) is hydrogenated over PVC (40 mg) at 1 atm for 18 hours. The catalyst is filtered through Celite and the solvent is removed under reduced pressure to give 2-bipheny!-4-y!methy!-succinic acid 4-tert-butyl ester 1 -methyl ester. The enantiomers are separated by chϊral HPLC.
Next, 2-biphenyM-ylmethyl-succinic acid 4-tert-butyl ester 1-methyl ester (160 mg, 0.451 mmol) is added to trifluoroacetic acid (5 mL). After 10 minutes, the solvent is removed under reduced pressure. Methylene chloride is added and the solvent is removed under reduced pressure to give 2-biphenyl-4-ylmethyl-succinic acid 1 -methyl ester. This material is used directly in the subsequent coupling reaction.
Intermediate 16-1: Synthesis of (R)-ethyl 3-amino-4~{3'-chlorobipheny{-4~yi}butanoate hydrochloride
Figure imgf000220_0001
To (/?)-ethyJ 3-(tert-butoxycarbof»ylamino)-4-(3'-chlorobiphenyl-4-yl)butanoate (3.33 g, 7.97 mmol) is added a solution of 4 M HCI in 1,4-dioxane (19.9 mL, 18.0 mmol) at room temperature. After stirring for 0.5 hours, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride (2.90 g). HPLC retention time « 0.70 minutes (condition B); MS (m+1) = 318.26; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 - 1.24 (m, 3 H) 2.73 - 2.78 (m, 1 H) 2.84 - 2.91 (m. 1 H) 3.05 - 3.11 (m, 1 H) 3.50 - 3.54 (m, 1 H) 3.92 (br s, 1 H) 4.14 - 4.17 (m, 2 H) 7.29 - 7.53 (m, 8 H) 8.73 (br. s., 3 H).
Following intermediates are prepared using simifar procedure as described for intermediate 16-1:
Figure imgf000220_0002
Figure imgf000221_0001
Figure imgf000222_0002
Intermediate 16-7: (R)-benzyi 3-amino-4-(3'-chlorobiphenyt-4-yl)butanoate hydrochloride
Figure imgf000222_0001
To (R)-benzyl 3-(tert-butoxycarbonylamino)-4-(3'-chlorobiphenyl-4-yl)butanoate (3.561 g, 7.42 mmol) is added a solution of 4 M HCi in 1 ,4-dioxane (18.55 mL, 74.2 mmoϊ) at room temperature. After stirring for 4 hours, the reaction mixture is concentrated under reduced pressure to give (R)-benzyl 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride (3.11 g). HPLC retention time « 1.07 minutes (condition B); MS (m+1) « 380.1: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.81 (A of ABX1 Jab = 17.4 Hz, Jaκ - 4.5 Hz1 1 H) 2.93 (B of ABX, Λb = 17.4 Hz1 Jbx = 7,6 Hz, 1 H) 3.03 - 3.09 (m, 1 H) 3.50 (dd, J - 4.9 and 13.5 Hz1 1 H) 3.98 (br s, 1 H) 5.09 (s, 2 H) 7.24 - 7.22 (m, 9 H) 7.35 - 7.38 (m, 1 H) 7.42 (d, J * 8.1 Hz, 2 H) 7.48 - 7.49 (m, 1 H) 8.78 (br S1 3 H).
intermediate 17-1: Synthesis of (/?)-ethyl 3~(tert-butσxycarbonylamino)-4-<3'- chtorohipheny)-4~yl)butanoate
Figure imgf000223_0001
A mixture of (R)-ethyl 4-(4-bromophenyt)-3-(tert-butoxycarboπy!amtno)bυtanoate (4.89 g, 12.66 mmol), 3-chlorophenylboronic acid (2.97 g, 18.99 mrnol), Pd(PPh3J4 (1.463 g, 1.266 mmoi) and 2 M aqueous Na?CO3 (12.66 ml, 25.3 mmol) in 1 ,2-dimethoxyethane (100 ml) is allowed to stir at 95 °C under nitrogen for 3 hours. The reaction mixture is cooled to room temperature and quenched with brine. The two phases are separated. The mixture is extracted twice with ethyl acetate from the aqueous layer. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel flash column chromatography (heptane/BOAc = 100:0 to 70:30) to give (R)-ethyl 3-{tert-btrtoxycarbonylamino)-4-(3'~chlorob»phenyl~4- yl)butanoate (3.33 g); HPLC retention time = 1.44 minutes (condition B); MS (ES+) « 318.26 (m-BOC+2; 100%); 1H NMR (400 MHz1 CHLOROFORM-d) δ ppm 1.28 (t, J = 7.2 Hz, 3 H) 1.41 (S, 9 H) 2.47 (A of A8X, Jat> - 15.8 Hz, J3* ~ 5.9 Hz, 1 H) 2.52 (B of ABX, Jab « 15.8 Hz1 Jbx - 5.4 Hz, 1 H) 2.83 - 2.89 (m, 1 H) 2.95 - 3.00 (m, 1 H) 4.17 (q, J = 7.2 Hz1 2 H) 4.18 (br s. 1 H) 5.07 (br S1 1 H) 7.26 - 7.37 (m, 4 H) 7,43 - 7.51 (m. 3 H) 7.55 (br t, J = 1 ,8 Hz, 1 H).
Following intermediates are prepared using similar procedure as described for intermediate 17-1:
Figure imgf000223_0002
Figure imgf000224_0001
Figure imgf000225_0001
Intermediate 17-2: (R)-benzy! 3-(tert-butoxycarbonylaminoH-(3'-chlorobiphenyl~4- yt)butanoate
Figure imgf000226_0001
A suspension of give (R)-benzyl 4-(4-bromophenyl)-3-(tert~butoxycarbonylamino)butanoate (2.00 g, 4.46 mmol), 3-chlorophenylboronic acid (1.046 g, 6.69 mmol), Pd(PPh3)4 (0.515 g< 0.446 mmol) and Na2CO3aq (4.46 ml, 8.92 mmol) in Toluene (30 ml) is allowed to stir under nitrogen at 95 °C for 19 hr. The reaction mixture is cooled to ambient temperatυrev and diluted with brine and EtOAc. The products are extracted twice with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The residue is purified by flash column chromatography on 90 g silica ge) (eluent: heptane/EtOAc = 100:0 to 65:35) to give (R)- benzyl 3-(tert-butoxycarbonylamino)-4'(3'-ch}orobiphenyl-4-yl)butanoate (1.03 g); HPLC retention time = 174 minutes (condition B); MS (ES+) = 380.2 (m~BOC+2; 100%); 1H NMR (400 MHz1 CHLOROFORM-^ δ ppm 1.40 (s, 9 H) 2.52 (A of ASX1 JΛ - 15.9 Hz1 Jn « 5.8 Hz, 1 H) 2.58 (B of ABX1 J& = 15.9 Hz, J* = 5.6 Hz, 1 H) 2.81 - 2.98 (m, 2 H) 4.19 (br s, 1 H) 5.07 (br d, 1 H) 5.12 (A of AB1 J * 12.3 Hz, 1 H) 5,17 (A of AB, J * 12.3 Hz1 1 H) 7.20 ~ 7.22 (m, 2 H) 7.28 - 7.39 (m, 7 H) 7.42 - 7.47 <m, 3 H) 7.53 ~ 7.54 (m, 1 H).
Intermediate 18: Synthesis of (S)-benzyl 1-(2-tert-bυtoxy-2-oxoethyJ)pyrrolidine-2- carboxylate
Figure imgf000226_0002
To a suspension of (S)-benzyl pyrrolidine-2-carboxylate hydrochloride (700 mg, 2.90 mmol) and K5CO3 (1201 mg, 8.69 mmot) in DMF (7 ml), t-butyl bromoacetate (0.535 ml, 3.62 mmol) is added. After stirring for 71 hours, aqueous K2CO3 (1.5 g of K?CO3 / 40 ml of H2O) is added to the reaction mixture. The products are extracted with EtOAc. The organic layer is washed twice with water and once with brine, dried over K^COs, filtered, and concentrated to give (S)-benzyl 1-(2-tert-butoxy-2-oxoethyl)pyrrolidine-2-carboxylate (458 mg); HPLC retention time = 1.38 minutes (condition D); MS (m+1) » 320,2; 1H NMR (400 MHz, CHLOROFORMS δ ppm 1.44 (s, 9 H) 1.81 - 2.03 (m, 3 H) 2.13 - 2.14 (m, 1 H) 2.82 - 2.88 (m, 1 H) 3.13 - 3.17 (m, 1 H) 3.46 (A of AB1 J = 17.3 Hz, 1 H) 3.49 (B of AB, J = 17,3 Hz1 1 H) 3.73 {ύd, J = 8.8 and 4.8 Hzt 1 H) 5.15 (A Of AB1 J a 12,4 Hz, 1 H) 5.17 (B of AB1 J * 12.4 Hz, 1 H) 7.29 - 7.38 (m, 5 H).
Intermediate 19: Synthesis of (R)-ethyl 3-(tert-butoxycarbonylamino)-4~(2\5'- dichlorobiphenyl-4-yl)butanoate
Figure imgf000227_0001
A mixture of (R)-ethyl 4-(4-bromophenyO-3-(tert-butoxycarbonylamino)butanoate (1.005 g, 2.60 mmol), 2,5-dichlorophenylboronic acid (0.745 g, 3.90 mmol), Pd(PPh3)4 (0.301 g, 0.260 mmoO and 2 M aqueous Na2CO3 (2.60 mi, 5.20 mmol) in 1 ,2-dimethoxyethane (20 ml) is allowed to stir at 95 °C under nitrogen for 3 hours. The reaction mixture is cooled to room temperature and diluted with brine. The two phases are separated. The products are extracted twice with ethyl acetate (2 x 100 mi) from the aqueous layer. The combined organic layer is washed with brine, dried over MgSO,*, filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc = 100:0 Io 70:30) to give (R)~etby\ 3-(tert- bυtoxycarbonylamino)-4-(2',5'-dichlorobJphenyf-4-yObutanoate (1.09 g); HPLC retention time - 1.50 minutes (condition B); MS (ES+) = 352.00 (m-BOC+2; 100%); 1H NMR {400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J= 7.1 Hz, 3 H) 1.41 (s, 9 H) 2.45 ~ 2.58 (m, 2 H) 2.85 - 3.00 (m. 2 H) 4.17 (t, J = 7.1 Hz, 2 H) 4.20 (br s, 1 H) 5.06 - 5.08 (m, 1 H) 7.23 - 7.28 (m, 3 H) 7.31 - 7.40 (m, 4 H).
Intermediate 20: Synthesis of (R)-3-am«no-4-(3'-chlorobiphenyI-4-yi)butanoic acid hydrochloride
Figure imgf000228_0001
A solution of (R)-benzyl S-Uert-butoxycarbonyiaminoM-^'-chlorobipheny^yObutanoate (152 mg, 0.317 mmol} and 1 M aqueous NaOH (1.583 ml, 1.583 mmoi) in a mixed sofvent of MeOH (0.3 ml) and THF (3 ml) is allowed to stir for 2 hours. The reaction is quenched with 1M aqueous HCI (2.5 ml). The products are extracted with EtOAc. The organic tayer is dried over Na2SO4, filtered, and concentrated to give crude.
To the crude, a solution of 4 M HCI in 1,4-dioxane (1.583 mi, 6.33 mmol) is added. After stirring for 1 h, the precipitated solid is collected, and dried under reduced pressure to give (R)-3-amino-4-(3'-chlorobiphenyl-4-yi)butanoic acid hydrochloride (60.2 mg) as a white solid; HPLC retention time * 0.52 minutes (condition B); MS (m+1) = 290.22; 1H NMR (400 MHz, CD3OD) 6 ppm 2.58 - 2.74 (m, 2 H) 2.99 - 3.11 (m, 2 H) 3.80 - 3.85 (m, 1 H) 7.34 - 7.45 (m, 4 H) 7.54 - 7.57 (m, 1 H) 7.62 - 7.65 (m, 3 H).
Intermediate 21: Synthesis of a mixture of 1-(2-(benzyloxy)-2- oxøethyl)cyclopentanecarfooxyJ/c acid and 2-(1-(bβnzyloxycarbcnyl)cyc!opentyl)aeetic acid
Figure imgf000228_0002
A solution of 2-oxaspiro[4.4]nonane-1,3-dione (3 g, 19.46 mmol) and benzyl alcohol (2.023 ml, 19.46 mmol) in toluene (2 ml) is allowed to stir at 100 °C for 19 hours. The reaction mixture is cooled to ambient temperature and concentrated to give 6:1 mixture of 1-(2- {benzy(oxy)-2-oxoethy{)cycfopentanecarboxylfc acid and 2-(1-
(benzyloxycarbonyl)cyclopentyl)acetic acid (4.89 g); 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.60 - 1.78 (m, 6 H) 2.19 ~ 2.24 (m, 2 H) 2.75 (s, 2 H) 5.11 (s, 2 H, major isomer) 5.13 (S1 2 H, minor isomer) 7.30 - 7.37 (m, 5 H). Intermediate 22: Synthesis of tert-butyl 4-(biphenyl-4-yf)-3-(tβrt- butoxycarbonylamino)butanoate
Figure imgf000229_0001
A solution of 4-(bJphenyl-4-yl)-3-(tert-butoxycarbonyiamino)butanoic acid (250 mg, 0.703 mmoi), tBuOH (0.135 ml, 1.407 mmol), EDCI (270 mg, 1.407 mmol) and 4- dimethylaminopyridine (86.0 mg, 0.704 mmol) in DCM {7 ml) is allowed to stir at room temperature under nitrogen for 62 hours. The reaction is quenched with water, and the organic layer is separated and concentrated. The residue is purified by flash column chromatography on silica gel to give tert-butyl 4-(biphenyl-4-yl)-3-(tert- butoxycarbonylamino)bu.anoate (110 mg) ; HPLC retention time = 1.77 minutes (condition B); MS (ES+) = 412.1 (m+1) 300.0 (m-tBux2+3; 100%); 1H NMR (400 MHz1 CHlOROFORM-d) δ ppm 1.41 (s, 9 H) 1.47 (s, 9 H) 2.36 (A of ABX, J06 * 15,5 Hz, J^ = 6.2 Hz, 1 H) 2.44 (B of ABX, Jab = 15.5 Hz, Jbx = 5.6 Hz) 2.82 - 2.94 (m, 2 H) 4.11 - 4.17 (m, 1 H) 5.08 - 5.10 (m, 1 H) 7.25 - 7.34 (m, 3H) 7.41 - 7.44 (m, 2 H) 7.51-7.58 (m, 4 H).
Intermediate 23: Synthesis of ethyl 3^mino~4-{3'-chloro~3-fluorobiphenyl<4- yl)biitanoate
Figure imgf000229_0002
A suspension of zinc (479 mg, 7.33 mmol) and 1 ,2-dibromoethane (0.032 ml, 0.366 mmol) in THF (8 ml) is heated at 70 °C under nitrogen then a few drops of ethyl bromoacetate is added. After stirring for 20 min, a solution of 2-(3'-chloro-3-fiuorobφhenyl-4-yl)acetonitr)le (300 mg, 1.221 mmol) in THF (2 ml) is added in one portion. The remaining bromoacetate is added dropwise over 50 min (total amount of ethyl bromoacetate: 4.88 mmol). After stirring for 15 min at the same temperature, the reaction mixture is coofed to ambient temperature. To the reaction mixture, sodium triacetoxyborohydride (2588 mg, 12.22 mmol) and AcOH (8 ml) are added. The reaction mixture is allowed to stir for 13 hours, and concentrated to give crude. The crude is diluted with EtOAc, and 2M aqueous Na^CO3 is added to be pH of 10. The products are extracted with EtOAc. The organic layer is dried over K2CO3, filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% NH4OH) to 100% MeCN to give ethyl 3-amino-4-(3'- chtoro~3-fluorobiphenyl-4-yi)butanoate (148 mg) as orange oil; HPLC retention time * 0.85 minutes (condition B); MS (m+1) = 336.13; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.36 (A of ABX, Jsb = 15.9 Hz, Jn « 8.8 Hz, 1 H) 2.52 (B of ABX, Jab * 15.9 Hz, Λx = 4.0 Hz, 1 H) 2.71 - 2.76 (m, 1 H) 2.82 - 2.87 (m, 1 H) 3.51 - 3.57 (m, 1 H) 4.15 (d, J - 7.1 Hz, 2 H) 7.24 - 7.39 (m, 5 H) 7.42 - 7.44 (m, 1 H) 7.54 - 7.55 (m, 1 H).
Intermediate 24: Synthesis of 2«(3'-chlorø-3-fluorobiphenyl-4-yl}acetonUrile
Figure imgf000230_0001
F
A suspension of 4-bromo-2-fluorobenzyl cyanide (3.50 g, 16.35 mmol), 3- chlorobenzeneboronic acid (2.68 g, 17.17 mmol), Pd(OAc)? (0.110 g, 0.491 mmol), K2CO3 (5.65 g, 40.9 mmol) and tetrabutytammonium bromide (5.80 g, 17.99 mmol) in water (14 m() is allowed to stir under nitrogen at 70 °C for 1 hour. The reaction mixture is cooled to room temperature, and diluted with EtOAc. The two phases are separated. The organic layer is washed with brine, dried over Mg$O«, filtered and concentrated. The obtained residue is purified by sύ' lca gef flash column chromatography (heptane/EtOAc - 100:0 to 70:30) to give 2-(3'~chloro-3-fluorobiphenyl-4~yl)acetonitrile (3.52 g); HPLC retention time = 1.17 minutes (condition B); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.81 (S1 2 H) 7.29 ~ 7.45 (m, 5 H) 7.50 - 7.55 (m, 2 H).
Intermediate 25: (R)-tert-butyS 4-(1-{4-bromophenyl)-4-ethoκy-4-oxobutan-2-ylammo)- 4-oxobutanoate
Figure imgf000230_0002
To a solution of 4-tert-butoxy-4-oxobutanoic acid (2.38 g, 13.64 mmol) in DMF (30 mL) and DChA (30 mL) is added (R)-ethyl 3-amino-4-(4-bromophenyl)bυtanoate hydrochloride (4 g, 12.4 mmol), HATU (5.19 g, 13.64 mmol), and TEA (6.91 mL, 49.6 mmol). After stirring at room temperature for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc1 the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (R)-tert-butyl 4-(1-(4-bromophenyl)-4-ethoxy-4- oxobutan-2~ylamino)-4-oxobutanoate (4.0 g). HPLC retention time = 1.70 minutes (condition A)1 MS (m+1) * 444.1.
Intermediate 26: (R)-3-amino-4-(5'-fiuoro-2'-methoxy"biphenyl-4-yl)-bulyHc acid ethyl ester hydrochloride salt
Figure imgf000231_0001
To a solution of (R)-ethyl 4-(4-bromophenyi)-3-(tert-butoxycarbonylamino)butanoate, (3.12 g, 8.08 mrnol), and 5-fluoro-2-methoxyphenyiboronic acid (2.2 g, 12.93 mmol) in toluene (52 mL) and is added PdCI2(dppf) CH2CI2 adduci (0.66 g, 0.81 mmol) and 2M aq. Na2CO3 (8.1 mL, 16.16 mmof). After stirring at 95 °C under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with ice water. The crude is diluted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc = 100:0 to 50:50) to give (R)-ethyl 3- (tert-butoxycarbonylamino)-4-(5'-fluoro-2'-methoxybiphenyl-4-yl)butanoate (2.86 g). HPLC retention time - 1.80 minutes (condition A); MS (m+1) ~ 432.2; 1 H NMR (400 MHz, CHLOROFORM-d) S ppm 1.31 (t, J=7.1 Hz1 3 H) 1.45 (s, 9 H) 2.45 - 2.65 (m, 2 H) 2.83 - 2.94 (m. 1 H) 2.94 - 3.09 (m, 1 H) 3.80 (S, 3 H) 4.20 (q, J-12 Hz, 2 H) 4.24 - 4.33 (m, 1 H) 5.11 (br. s., 1 H) 6.90 - 6.96 (m, 1 H) 7.00 (dd, >7.8, 3.3 Hz. 1 H) 7.06 (dd, J=9.2, 3.2 Hz, 1 H) 7.27 (d, J=7.8 Hz, 2 H) 7.49 (d, >7.8 Hz1 2 H)
A solution of (R)-ethyl 3-{tert-butoxycarbonylaminoM-(5'-fluoro-2'-methoxybiphenyl-4- yl)butanoate, (2.86 g, 6.62 mmol) in 4M HCI in 1,4-dioxane (33.1 ml, 132 mmol) is stirred at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to gh/e (R)-ethyl 3-amino-4-(5'-fluoro-2'-methoxybiphenyl-4-yl)butanoate hydrochloride salt (2.44 g). HPLC retention time « 1.46 minutes (condition A); MS (m+1) = 332.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (t, J=6Λ Hz, 3 H) 2.66 - 2.77 (m. 1 H) 2.78 - 2.91 (m, 1 H) 2.94 - 3.10 (m, 1 H) 3.42 - 3.53 (m, 1 H) 3.67 (s, 3 H) 3.83 - 3.96 (m, 1 H) 4.07 (q, J=6.8 Hz, 2 H) 6.77 - 6.84 (m, 1 H) 6.87 - 6.96 (m, 2 H) 7.23 (d, J*7.1 Hz, 2 H) 7.38 (d, J=7.1 Hz, 2 H) 8.64 (br. s., 2 H)
Intermediate 27: (R)-ethyl 4-(3'~ch!orobiphenyl-4 y!)-3-(2-ethoxy-2- oxoacetamido)butanoate
Figure imgf000232_0001
To a solution of (R)-ethyl 3-amino-4-(3*-chloiObipnenyil-4-yl)butanoate hydrochloride (500 mg, 1.57 mmol) in DMF (11 mL) is added TEA (0.23 ml, 1.65 mmoi) and ethyl 2-chloro-2- oxoacetate (0.18 mL, 1.57 mmol) at room temperature. After stirring for 1 hour at room temperature, the reaction is quenched with HzO1 and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc = 70:30 to 50:50) to give (R)-ethyl 4-(3'~ch)orobiphenyl-4- yl)-3-(2-ethoxy-2-oxoacetamido)butanoate (550 mg). HPLC retention time « 1.88 minutes (condition A); MS (m+1) - 418.3
Intermediate 2β: (R)-ethyl 4^3>-chlorobiphenyl-4-yl)-3-(2-hydraziny!-2- oxoacetamido)butanoate
Figure imgf000232_0002
To a solution of (R)-ethyl 4-(31-chlσrobiphenyl~4-yl)-3-(2-ethoxy-2-oxoacetamido)butanoate (450 mg, 1.08 mmol) in MeOH (24 ml) is added a solution of 50% wt hydrazine (0.068 ml, 1.08 mmol) in MeOH (10 mL) at -2O°C. After stirring for 18 hours at room temperature, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 4-(3'- chlorobiphenyl*4-yl)-3-(2-hydrazinyl-2-oxoacetamido)butanoate (412 mg). HPLC retention time ~ 1.76 minutes (condition A); MS (m+1) « 404.1
Intermediate 29: {R)~ethyl 4-(3'-chlorobJphenyl«4-y})-3-(2-methoxythJazole-5- carboxamido)butanoate
Figure imgf000233_0001
To a solution of 2~methoxythiazole~5-carboxylic acid (80 mg, 0.50 mmol) and (R)-βthyl 3- aminc~4-(3'~chlorobiphenyl-4-yi)butanoate hydrochloride (160 mg, 0.45 mmol) in DMF (5 mL) is added HATU (207 mg, 0.55 mmol) and TEA (276 mg, 2.73 mmol). The crude is stirred at room temperature for 2 hrs. The crude is neutralized with 1 N HCI and diluted in water and EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane to give (R)-ethyl 4-(3'-chlorobiphenyl-4-yl)-3-(2-methoxythiazole-5- carboxamido)butanoate (170 mg). HPLC retention time ~ 1.97 minutes (condition D); MS (m+1) = 459.1. 1H NMR (400 MHz1 CHLOROFORM-c/) δ ppm 1.29 (t, J*7.1 Hz, 3 H) 2.49 - 2.69 (m, 2 H) 2.93 (dd, J=13.6, 8.1 Hz1 1 H) 3.10 (dd, ./=13.5, 6.2 Hz, 1 H) 4.09 (S1 3 H) 4.00-4.15 (m, 2 H) 4.53 - 4.69 (m, 1 H) 6.78 (d, J-8.6 Hz, 1 H) 7.25 - 7.32 (m, 3 H) 7.35 (t, J=7.71 Hz, 1 H) 7.44 (dt, J-7.6, 1.5 Hz, 1 H) 7.48 - 7.54 (m, 3 H) 7.55 (t, J=1.8 Hz, 1 H). lntermediate 30: (R)-ethyl 4-(3'-chlorøbiphβnyl«4-yl)-3-(2-methoxyoxa2θte-5- carboxamtdo)butanoate
Figure imgf000234_0001
To a solution of 2-methoxyoxazole-5-carboxylic acid, intermediate 16, (98 mg, 0.69 mmol) and (f?)-ethy! 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride (210 mg, 0.57 mmoi) in DMF (10 mL) and CH2CI2 (4 mL) is added HATU (272 mg, 0.72 mmol) and TEA (0.50 mL, 3.58 mmol). The crude is stirred at room temperature for 2 hrs. The crude is quenched with water and diluted in EtOAc. The organic layer is washed with water 3X, brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane to give (R)-ethyl 4-(3'- chlorobiphβnyl-4-yl)-3-(2-methoxyoxa2θle'5-carboxamtdo)butanoate (122 mg). HPLC retention time = 1.89 minutes (condition A); MS (m+1) - 443.2; 1H NMR (400 MHz1 CHLOROFORM-d) δ ppm 1.28 (t, J-7.1 Hz, 3 H), 2.52 - 2.66 (m, 2 H), 2.94 (dd, 1 H), 3.08 (dd, J=13.6, 6.3 Hz, 1 H), 4.12 <s, 3 H), 4.14 - 4.23 (m, 2 H), 4.60 - 4.71 (m, 1 H), 6.81 (d, J=8.8 Hz, 1 H), 7.25 - 7.32 (m, 3 H)1 7.35 (t, J~7J Hz1 1 H)1 7.42 (S1 1 H), 7.43 - 7.47 (m, 1 H), 7.48 - 7.54 (m, 2 H), 7.55 (t, J=I .6 Hz, 1 H).
intermediate 31: 6-(methylsulfonamido)nicotinic acid
Figure imgf000234_0002
To a solution of methyl 6-aminonicotinate (1.0 g. 6.57 mmoi) in CH2CI2 (50 mL) with TEA (0.96 mL, 6.90 mmol) cooled in an ice bath is added MsCI (0.54 mL, 6.90 mmol) slowly. The crude is allowed to stir at room temperature for 2 hrs. The crude is then concentrated. The crude is dissolved in MeOH (20 mL) and to the crude is added 1 N NaOH (30 mL, 30 mmol). The crude is stirred at room temperature for 18 hrs, The crude is quenched with 1 N HCi (32 ml, 32 mmol). The crude is concentrated to remove MeOH and some water is removed as well. The crude is diluted in CH2CI2 and basified with 1 N NaOH (30 mL). The aq. layer is extracted with CHxCi2. The aq. iayer is acidified with concentrated HCI to bring the PH to 1 via PH paper indicator. The crude is diluted in EtOAc and the aq. Iayer is extracted with EtOAc. The combined organic Iayer is washed with brine, dried over MgSO4, filtered, and concentrated to give 6-(methylsuifonamido)nicotinic acid (421 mg) as a yellow solid. HPLC retention time - 0.40 minutes (condition D); MS <m+1) « 217.2.
Intermediate 32: 2>methoxyoxazoie~5-carboxylic acid
Figure imgf000235_0002
To a solution of ethyl 2-chlorooxazole-5-carboxylate (510 mg, 2.90 mmol) in anhdryous MeCN (10 mL) and anhydrous MeOH (10 mL) is added NaOMe (628 mg, 11.62 mmol), The crude is stirred at reflux for 2 hrs. To this crude is added additional MeOH. The crude is refluxed for another 4 hrs. The crude is concentrated and is redissolved in MeOH (10 mL). To this crude is added 1 N NaOH (10 ml). The crude is stirred at room temperature for 3 hrs. The crude is quenched with concentrated HCI, PH adjusted to 7 via PH paper indicator. The crude is concentrated and diluted in water. The aq. layer is acidified with concentrated HCI and diluted in EtOAc. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated to give2-methoxyoxazoie-5-carboxylic acid (290 mg). HPLC retention time ~ 0.58 minutes (condition D); MS (m+1) - 144.0.
intermediate 33: ethyl 5-oxo-4,5«dihydro-1,2,4-oxadiazole-3-carboxy!ate
O
Figure imgf000235_0001
To a solution of ethyl 2-(hydroxyamino)-2~iminoacetate (2 g. 15.14 mmol) in dioxane (15.00 mL) is added CDI (2.7 g, 16.65 mmol) and DBU (2.5 ml, 16.65 mmol) at room temperature. After stirring for 1 hour at 80°C, the reaction is quenched with 1N HCI1 and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give ethyl 5-oxo-4,5-djhydro-1,2,4-oxadιazole-3- carboxytate (2 4 g). HPLC retention time ~ 0.72 minutes (condition D); MS 159 1 (M+t).
Intermediate 34: 5-oxo-4,S-dihydro-1,2,4-oxadiazole-3-carboxylic acid
Figure imgf000236_0003
To a solution of crude ethyl 5-oxo-4,5-dihydro-1 ,2,4~oxadιazole-3-carboxylate (2 4 g, 15 14 mmol) in MeOH (2 mL) is added aqueous 1N NaOH (4 mL, 4 mmol) at room temperature. After stirring for 5 hours at room temperature the reaction is quenched with 1N HCI (5 mL, 5 mmol), the crude is concentrated under reduced pressure to remove MeOH The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na5SO4, filtered and concentrated under reduced pressure to give 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3- carboxylic acid (1 9 g)
Intermediate 35: 2-oxo«2,3-dihydrooxazoie-4-carboxylic acid
Figure imgf000236_0001
This intermediate is prepared according to Okonya, J. F,; Hoffman, R V , Johnson. M. C , J 0(y. Chem. 2002, 67, 1102-1108.
Intermediate 36: 3-hydroxyisothiazole~5-carboxylic acid
Figure imgf000236_0002
To a solution of methyl 3-hydroxyιsothιazote-5-carboxyiate (300 mg, 1 73 mmol) in MeOH (2 mL) is added 1N NaOH (6 mL, 6 mmol) After stirring at room temperature for 2 hours, the crude is concentrated under reduced pressure to remove MeOH and is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give S-hydroxyisothiazole-S-carboxylic acid (250 mg) lntermediate 37: ethyl 2-vtnyloxazole-5-carboxylate
Figure imgf000237_0002
To a solution of tributyl{vinyl)stannane (1.1 mL, 3.83 mmol) and ethyl 2-cNorooxazole-5- carboxylate (546 mg, 3.11 mmol) in dioxane (37 mL) is added Pd(PPh3J2CI2 (222 mg, 0.32 mmol) at room temperature. After stirring at 100 °C under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with H2O. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography (eluent: heptane/EtOAc = 90:10 to 80:20) to give ethyl 2-vinyloxazote-δ-carboxylate (470 mg). HPLC retention time - 0.39 minutes (condition B); MS (m+1) = 168.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.38 (t, ./=7.1 Hz, 3 H) 4.38 (q, J=7.2 Hz, 2 H) 5.88 (d, J=11.4 Hz, 1 H) 6.39 (d, J=17.7 Hz, 1 H) 6.69 (dd, J=17,6, 11.2 Hz1 1 H) 7.83 (s, 1 H)
intermediate 38: ethyl 2-ethyloxazole-5~carboxylate
Figure imgf000237_0003
To a solution of ethyl 2-vinyloxazole-5-carboxylate (470 mg, 2.81 mmol) in MeOH (7 mL) is added 10% wt. Pd/C (100 mg, 0.094 mmol) at room temperature. After stirring at room temperature under a balloon of hydrogen for 1 hour, the crude is filtered to remove Pd/C. The filtrate is collected and concentrated to give ethyl 2-ethyloxazole-5-carboxylate (470 mg). HPLC retention time ~ 1.09 minutes (condition A); MS (m+1) ~ 170.3; 1H NMR (400 MHz1 CD3OD) δ ppm 1.35 (t, J=7,6 Hz, 3 H) 1.36 (t, J=7.2 Hz, 3 H) 2.87 (q, J-7.7 Hz, 2 H) 4.35 (q, J-7.2 Hz, 2 H) 7.71 (s, 1 H)
Intermediate 39: 2-ethyloxazole-S-carboxylϊc acid
Figure imgf000237_0001
To a solution of 2-ethyloxazole-5-carboxylate (470 mg, 2.81 mmol) in MeOH (10 mL) is added 1 N NaOH (6 mL, 6 mmol). After stirring at room temperature for 18 hours, the crude is concentrated under reduced pressure to remove MeOH and is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-ethyloxazole-5-carboxylfc acid (244 mg). 1 H NMR {400 MHz, CD3OD) δ ppm 1.36 (t, >7.7 Hz, 3 H) 2.89 (q, J=7.6 Hz1 2 H) 5.15 (br. β., 1 H) 7.69 (s, 1 H)
intermediate 40: ethyl 2-vinylthiazole-5-carboxylate
Figure imgf000238_0001
To a solution of tributyl(vinyl)stannane (0.92 ml_, 3.14 mmol) and ethyl 2-bromothiazole-5- carboxylate (0.38 mL, 2.54 mmoi) in dioxane (33 mL) is added Pd(PPh3J2CI2 (182 mg, 0.26 mmol) at room temperature. After stirring at 100 °C under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with H2O. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over NajSO,,, filtered and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc = 90:10 to 80:20) to give ethyl 2-vinylthtazole-5- carboxylate (418 mg). HPtC retention time ~ 0.45 minutes (condition B); MS (m+1) = 184.1 ; 1H NMR (400 MHz, CD3OD) δ ppm 1.37 (t, J=7.2 Hz, 3 H) 4.35 (q, J-7.1 Hz, 2 H) 5.71 (d, J=10.9 Hz, 1 H) 6.24 (d, J=17.4 Hz, 1 H) 6.93 (dd, J=17.4, 10.9 Hz, 1 H) 8.29 (s, 1 H)
intermediate 41 : ethyl 2~ethylthiazole-5~carboxylate
Figure imgf000238_0002
To a solution of ethyl 2-viny!thiazole-5-carboxylate (400 mg, 2.18 mmol) in MeOH (7 mL) is added 10% wt. Pd/C (267 mg, 0.25 mmol) at room temperature. After stirring at room temperature under a balloon of hydrogen for 1 hour, the crude is filtered to remove Pd/C. The filtrate is concentrated to give ethyl 2-ethylthiazole-5-carboxylate (404 mg). HPLC retention time = 0.60 minutes (condition B); MS (m+1) « 186.3; 1H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.3 Hz1 2 H) 1.39 (t, J=7.20 Hz, 2 H) 3.07 (q, J-7.58 Hz, 2 H) 4.35 (q, J=7.16 Hz, 2 H) 8.22 (s, 1 H) lntermediate 42: 2-ethylthiazole-5-carboxylic acid
Figure imgf000239_0002
To a solution of ethyl 2-ethylthiazoie-5-carboxylate (400 mg, 2.159 mmol) in MeOH (10 mL) is added 1N NaOH (6 mL, 6 mmol) After stirring at room temperature for 18 hours, the crude is concentrated under reduced pressure to remove MeOH. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-ethylthiazo!e-5-carboxyiic acid (282.4 mg). HPLC retention time - 0.78 minutes (condition D); MS (m+3) « 160.4; 1H NMR (400 MHz, CD3OD) δ ppm 1.40 (t, J-7,6 Hz, 3 H) 3.07 (q, J=7.6 Hz1 2 H) 5.08 (br. s., 1 H) 8.20 (s, 1 H).
Intermediate 43: 3-Hydroxy-isoxazote-5-carboxylic acid
Figure imgf000239_0003
To a solution of S-hydroxy-isoxazole-δ-carboxylic acid methyl ester (286 mg, 2.0 mmol) in methanol (7 mL) is added 1N NaOH (4.0 mL, 4.0 mmol) and the mixture is stirred at room temperature for 18 hrs. The solvent is removed under reduced pressure and 4.0 mL of 1N HCI is added to the residue. The resulting solution is tyophilized to give the product which is used as is in subsequent reactions.
intermediate 44: δ-ffiethoxycarbonyimethyl-furan^-carboxyjic acid
Figure imgf000239_0001
To a solution of δ-methoxycarbonylmetriyl-furan^-carboxylic acid methyl ester (250 mg,
1.26 mmol) in methanol (5 mL) is added 1 N NaOH (2.78 mL, 2.78 mmol) and the mixture is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and 2.78 mL of 1N HCi is added to the residue. The resulting solution is lyophilized to give 5- carboxymethyl-furan-2-carboxylic add.
Next, to a solution of the above diacid (220 mg, 1.29 mmol) in methanol (8 mL) is added
Amberlyst-15 resin (50 mg) and the mixture is stirred at room temperature for 18 hours. The resin is filtered and the solvent is removed under reduced pressure to give the product which is used as is in subsequent reactions. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3,75 (s, 3H)1 3.82 (s, 2H), 6.45 (d, J=3.54 Hz, 1 H)1 7,29 (d, J=3.54 Hz1 1 H). 10.17 (s. broad, 1H).
Intermediate 45: (R)-4-(3'-Chloro-biphenyl-4-yl)-3-isocyanato-butyric acid ethyl ester
Figure imgf000240_0001
To a vigorously stirred mixture of 8% aqueous sodium bicarbonate (3 ml.) and methylene chloride (3 mL) at 0 °C is added triphosgene (28.1 mg, 0.095 mmoi) and the mixture is stirred at 0 °C for 5 minutes then Intermediate 17-1 (100 mg, 0.284 mmol) is added and stirring is continued for an additional 15 minutes. The organic layer is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound. This is used as is in subsequent reactions.
Intermediate 46: 2-(4-Methoxy-benzyl)«2H«tetrazote«5«carbonyl chloride
Figure imgf000240_0002
To a solution of 1 H-tetrazole-5-carboxylic acid ethyl ester sodium salt (500 mg, 3.05 mmol) in DMF (5 ml) at room temperature is added 4-methoxybenzyl chloride (747 μl, 5.48 mmol) and TEA (1500 μl, 10.76 mmol). The reaction mixture is stirred at room temperature overnight. The reaction is added water and extracted with EtOAc. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (10% to 30% EtOAc/Heptane), To a solution of the purified residue in EtOH (2 ml) at room temperature is added NaOH (2 ml, 2.000 mmol) and the mixture is stirred at room temperature. After stirring for 1 hour, the mixture is concentrated under reduced pressure to remove EtOH and extracted with EtOAC after being acidified to pH <5. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(4-methoxy-benzyl)-2H~tetrazole-5 -carboxyϋc acid.
Next, to a mixture of 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid in Toluene (15 ml) at room temperature is added SOCI? (1 mi, 13.70 mmoi) and the mixture is heated at 80 °C for 3 hr. The reaction mixture is concentrated under reduced pressure to give the crude product , which is used without further purification.
Intermediate 47: (RJ-S-Amino^-P'-chloro-biphenyM-yO-butyric acid indan-5-yl ester
Figure imgf000241_0001
To a suspension of boc-{R)-3-amino-4-(4-bromo-phenyl)-butanoic acid (500 mg, 1.396 mmol) in THF (12 ml) at room temperature is added 5-indanol (187 mg, 1.396 mmol) and Ph3P (403 mg, 1.535 mmol). To the mixture at ice bath is added DIAD (0.326 ml, 1.675 mmol) and the mixture is stirred from ice bath to room temperature overnight. The reaction is concentrated under reduced pressure and purified by column chromatography (5% to 20% EtOAc/Heptane) to give 450 mg of solid. To a solution of the obtained solid (200 mg, 0.422 mmol) in DMF (5 ml) at room temperature is added 3-chlorophenylboronic acid (79 mg, 0.506 mmo!), tripσtassium phosphate (134 mg, 0.632 mmol) and Pd(PPh3),, (48.7 mg. 0.042 mmo!). The reaction is stirred at 100 °C overnight. The reaction is quenched by brine and is extracted with EtOAc. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (5% to 30% EtOAc/Heptane). To the obtained residue (143 mg, 0.283 mmol) in DCM (1 ml) at room temperature is added TFA (1 mL, 12.98 mmol) and the mixture is stirred at room temperature for 2 hours The mixture is concentrated to give the crude salt which is used dtrectiy without further purification HPLC retention time = 1.27 minutes (condition B); MS (m+1) = 406
intermediate 48: (R)-4-Biphenyi-4~yl-3-ureido-butyric acid ethyl ester
ElO
Figure imgf000242_0001
To a suspension of (R)-3-amιno-4-biphenyl-4-yl-butyrιc acid ethyl ester (200 mg, 0.625 mmol) in THF (10 ml) at 0 °C was added phenyl chloroformate (0.087 mi, 0688 mmol) and pyndine (0.126 ml, 1 563 mmol). The mixture is stirred at 0 °C for 5 mm then is warmed up to room temperature. LCMS monitored the reaction until it is complete The reaction is extracted with EtOAc. The combined organic layer is washed with 1N HCi, H2O1 sat aq NaHCO3 and brine and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude residue Next, to a solution of the obtained residue (0.252 g, 0.625 mmol) in DMSO (1 5 ml) at room temperature is added ammonium hydroxide (0 027 ml, 0 688 mmol). The reaction is stirred at room temperature 30 mm LCMS showed small desired product with big starting materia! so more ammontum hydroxide is added and the reaction is stirred at room temperature overnight until the reaction is complete. The reaction is extracted with EtOAc The combined organic layer is washed with H20, 1 N HCI1 H?0, 1 N NaOH and brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure The residue ts purified by column chromatography (2% to 6% EtOH/DCM) to give (R)-4-biphenyl- 4-yl-3~uretdo-butyrιc acid ethyl ester (169 mg) HPLC retention time = 1 04 minutes (condition B)1 MS (m-M) = 327.
Intermediate 49: (R)-3-am»no-4-(3'-chloro-biphenyl-4-yi)-2-hydroxy-butyric acid methyl ester hydrochloride
Figure imgf000243_0001
(R)-3-(4-Bromo-phenyl)-2-tert-butoxycarbony{amino-propioπic acid (4 0 g, 11.6 mmol), 3- chlorophenylboronic acid (2,36 g, 15 11 mmol), Pd(PPh3),, (0.067 g, 0 058 mmof) and 2M Na2CO3 aqueous solution (8.0 mL) are refluxed in 1 ,2-dιmethoxyethane (70 mL) for 2 5 h under N2atomosphere. After cooling to room temperature, the reaction mixture is diluted with EtOAc and washed with 1M HCi and brine. The organic layer is dried over Na?SO4 and cocentrated. The residue is purified by flash column chromatography (silica gel, DCM/10%MeOH in DCM = 100.0 to 0 100).to give (R)-2-tert-butoxycarbonylamtno-3-(3l- chloro-bιphenyl-4-yi)-propιonic acid (containing inpurities) HPLC retention time = 1,56 minutes (condition A). MS (m+1) - 376.
This is dissolved in 1, 2-dimethoxyethane (40 mL) and Et3N (1.46 mL, 10.5 mmol) and ethyl chloroformate (1.00 mL, 10 5 mmol) are added. After being stirred at room temperature for 0 5h, the resultant preαprtate is removed by filtration. To the filtrate is slowly added NaBH4 (0 44 g, 11 6 mmol) in H2O (5 mL) After being stirred for 2 h, the reaction mixture is diiuted with EtOAc and washed with H2O and brine. The organic layer ts dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluent, heptane/EtOAc = 100.0 to 0:100) to give [(R^-φ'-diioro-biphenyM-yO-1-hydroxymethyl- ethyl]~carbamic acid tert-butyl ester (2 8 g). HPLC retention time - 1 26 minutes (condition A): MS (m+1-Boc) * 262. 1 H-NMR (400 MHz1 DMSO-d6) δ ppm 1 43 (s. 9 H), 2 90 (d. 2 H, J = 7 33 Hz). 3.60 (dd, 1 H, J - 5 05, 10 86 Hz)1 3 72 (dd, 1 H1 J - 3 79, 11.12 Hz), 3.91 (be, 1 H)1 4.75 (be, 1 H), 7,29-7 34 (m. 3 H), 7.37 (t, 1 H, J = 7 83 Hz), 7.44-7 48 (m, 1 H), 7 51 (d, 2 H, J ~ 8 08 Hz), 7.57 (t, 1 H1 J = 1.77 Hz).
Next to a solution of [(R)-2-(3'-chloro-biphenyl-4-yl)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (2.0 g, 5.53 mmol) in DCM (30 mL) is added Dess-Martin periodinane (2 81 g, 663 mmol) After being stirred at room temperature for 2 h. the reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 aqueous solution and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography (silica gel, eiuent; heptane/EtOAc = 100.0 to OiOO) to give [(R)-2-(3'-chforo- biphenyi-4-yl)-1-formyl-ethyl]-carbamic acid tert-butyl ester (1.05 g). HPLC retention time = 1.27 minutes (condition A): MS (m+1) - 360.
This is dissolved in MeOH (20 mL) and AcOH (0.199 mL, 3.47 mmot). To this solution KCN (0.226 g, 3.47 mmol) in H2O (4 mL) is slowly addd. After being stirred at room temperature overnight, the reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 aqueous solution, H2O and brine. The organic layer is dried over Na2SO4 and concentrated. This is treated with 4M HCI in dioxane (20 mL) and MeOH (10 mL) at room temperature. After being stirred overnight, the reaction mixture is concentrated. The residue is dissolved in MeOH and treated with SOCI2 (0.211 mL, 2.89 mmoi). After being stirred at 5O°C for 5 h, the reaction mixture is concentrated to dryness, The residue is dissolved in THF (10 mL) and treated with saturated NaHCO3 aqueous solution (5 mL) and BoC2O (0.631 g, 2.89 mmol). After being stirred at room temperature for 2 h, the reaciton mixutre is diluted with EtOAc and washed with brine. The organic layer is dried over MgSO4 and concentrated. The residue is pύrifiied by flash column chromatography (silica gel, eluent; heptane/EtOAc = 100:0 to 0:100) to give (R)-3-tert-butoxycarbonylamtno-4-(3'-chloro-biphenyl-4-yl)-2-hydroxy- butyric acid methyl ester (0.61 g). HPLC retention time = 1.01, 1.06 minutes (condition B): MS (m+1-Boc) = 320. 1 H-NMR (400 MHz, CDCI3) 5 ppm 1.40 (s, 9 H), 2.77-3.05 (m, 2 H), 3.63 (S, 0.7 H), 3.77 (s, 2.3 H), 4.11 (s, 0.8 H), 4.25-4.40 (m, 1.2 H), 4.78-4.95 (m, 1 H)1 7.27-7.40 (m, 4 H). 7.42-7.58 (m, 4 H).
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-hydroxy-butyric acid methyl ester (113 mg, 0,269 mmol) is treated with 4M HCI in dioxane (2 mL). After being stirred at room temperature for 1h, the reaction mixture is concnetrated. The residue Is used for a next step without further purification. HPLC retention time = 1.22, 1.29 minutes (condition A): MS (m+1) ~ 320.
Intermediate SO: (R)-3~amino-4-(3'-chloro-biphenyl-4-yl)-2-methoxy-butyric acid methyl ester hydrochloride
Figure imgf000245_0001
To a solution of (R)-3-tert-bυtoxycart>onylamino-4-(3'-chloro-biphenyl-4-yf)-2-hydroxy-butyric acid methyl ester (610 mg, 1.45 mmol) in CH3CN (20 mL) are added iodomethane (0.545 mL, 8.72 mmol) and silver oxide (1.35 g, 5.81 mmol). After being stirred at room temperature for 16 h, additional iodomethane (0.545 mL, 8.72 mmol) and silver oxide (1.35 g, 5.81 mmol) are added and stirred for 3 days. The reaction mixture is filtered through celite pad and the filtrate is washed with brine. The organic layer is dried over MgSO4 and concnetrated. The residue is purified by flash column chromatography (silica gel, eluent; heptane/EtOAc = 100:0 to 0:100) to give (R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-methoxy~ butyric acid methyl ester (500 mg). HPLC retention time = 1.20, 1.25 minutes (condition B): MS (m+1-Boc) = 334. 1 H-NMR (400 MHz, CDCtø δ ppm 1.37, 1.41 (s, 9 H), 2.72-3.03 (m, 2 H), 3.43, 3.71 (s, 3H), 3.63-3.82 (m, 1 H)1 4,27-4.41 (m, 1 H), 4.68-5.04 (m, 1 H), 7.28-7.40 (m, 4 H), 7.41-7.61 (m, 4 H).
(R)-3-tert-butoxycarbony}amino-4-(3'-chloro-biphenyl-4-yl)-2-methoxy-butyric acid methyl ester (200 mg, 0.461 mmol) is treated with 4M HCI in dioxane (3 mL). After being stirred at room temperature for 1h, the reaction mixture is concnetrated. The residue is used for a next step without further purification. HPLC retention time = 1.26, 1.33 minutes (condition A): MS (m+1) = 334.
Intermediate 51 : (R)-3-amino-4-(3'-chloro-biphenyl-4-yl)'2-methoxy-butyric acid ethyl ester hydrochloride
Figure imgf000246_0001
To a solution of (R)-3-amino-4-(3'-chloro-bipheny!-4~yl)-2~methoxy-butyric acid methyl ester (500 mg, 1.15 mmol) in MeOH (5mL) is added 2M NaOH aqueous solution (5 mL). After being stirred at room temperature for 2h, the reaction mixture is acidified with 2M HCI and extracted with EtOAc. The organic layer is dried over Na2SO4 and concentrated. The residue is dissolved in EtOH (5 mL) and treated with SOC)2 (0.252 mL, 3.26 mmol). After being stirred at 55°C, the reaction mixture was cocentrated. The residue is used for a next step withour further purification. HPLC retention time - 1.49 minutes (condition A): MS (m+1) = 348.2
Intermediate 52: (R)-3-AmJno-4-{3'-chIoro-b}phenyJ-4-yl)-2"fluoro4)Utyr»c acid methyl ester hydrochloride
Figure imgf000246_0002
To a solution of (R)-3-tert-butoxycarbonylamino-4-{3'-chloro-biphenyl-4-yl)-2-hydroxy-butyric acid methyl ester (220 mg, 0.524 mmol) is added DAST (0.083 mL, 0.629 mmol) at O°C. The reaction mixture is gradually warmed to room temperature and stirred for 1 h. Additional DAST (0.083 mL, 0.629 mmol) is added and stirred at room temperature for 2 h. The reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 aqueous solution and brine. The organic layer is dried over Na?SO4 and concentrated. The residue is purified by flash column chromatography (silica gel, eluent; heptane/EtOAc = 100:0 to 0;100) to give (R)-3-tert-bυtoxycarbonylamino-4-{3'-cNoro-biphenyM-yI)-2-fluoro-butyric acid methyl ester (63 mg). HPLC retention time = 1.36 minutes (condition B): MS (m+1-Boc) ~ 322.1 H-NMR (400 MHz. CDCI3) δ ppm 1.39 (s, 9 H)1 2.84-2.95 (m, 2 H), 3.06 (bs, 0.5 H)1 3.69 (S1 3 H), 4.43-4.61 (m. 1 H), 4.72-4.80 (m, 0.5 H), 5.00 (s, 0,5 H)1 5.12 (s, 0.5 H), 7.28-7.34 (m, 3 H)1 7.37 (t, 1 H, J « 7.58 Hz), 7.42-7.47 (m. 1 H), 7.48-7.53 (m, 1 H), 7.55 (t, 1 H, J ~ 2.02 Hz). 19F-NMR (377 MHz, CDCI3) δ ppm -204.18.
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-fluoro-butyric acid methyl ester (60 mg, 0.142 mmol) is treated with 4M HCI in dioxane (1.5mL). After being stirred at room temperature for 1h, the reaction mixture is concnetrated. The residue is used for a next step without further purification, HPLC retention time - 0.88 minutes (condition B): MS (m+1) ~ 322.
Intermediate 53-1 : [(R)-I K3'-chtoro-biphenyM-ylmethyl)*3Hrιethanesuifonylamino~3~ oxo-propyl]-carbamic acid tert-butyl ester
Figure imgf000247_0001
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yf)-butyric acid ethyl ester (250 mg, 0.598 mmol) is treated with 2M NaOH aqueous solution (1 mL) in THF (1 mL) and EtOH (2 mL). After being stirred for 1h, the reaction miture is acidified with 1M HCI and extracted with EtOAc. The organic layer is washed with brine, dried over Na2SO4 and concentrated in vacuo. To a solution of this residue in DMF (2 mL) are added methylsulfonamide (85 mg, 0.897 mmol), EDC (172 mg, 0.897 mmol), HOAt (98 mg, 0.718 mmol), and Et3N (0.125 mL, 0.897 mmol). After being stirred at room temperature overnight, the reaction mixture is diluted with EtOAc, washed with 1M HCt and brine. The organic layer is dried over NaZSO4 and cocentrated. The residue is purified by flash column chromatograpy (silica gel, eluent: DCM/1G%MeOH in DCM = 100:0 to 0:100) to give [(R)-I -(3'-chlorc-bipnenyW-yimethyl)-3- methanesulfonylamino-3-oxo-propyO-carbamic acid tert-buty} ester (244 mg). HPLC retentions time = 1.30 minutes (condition B); MS (m+1) = 467; 1 H NMR (400 Mz, DMSO-d6) δ ppm 1.30 (S1 9 H), 2.41-2.48 (m, 2 H), 2.70-2.78 (m. 2 H), 3.1Θ (s, 3 H), 3.99-4.11 (m, 1 H), 7.28 (d, 2 H1 J - 8.34 Hz)1 7.38-7.44 (m, 1 H), 7.48 (t, 1 H1 J -7.83 Hz), 7.59-7.66 (m, 3 H), 7.69 (S, 1 H). Following compounds are prepared using similar procedure as described in example 53-1 :
Figure imgf000248_0002
Intermediate 64-1 : (R)-3-{2-(tert«bυtoxycarbonyl-ethoxycarbonylmethyl-am»no)- propionylamino]-4-(3'-chloro-biphenyl-4~yi)-butyric ac'd ethyl ester
Figure imgf000248_0001
To a suspension of 2-(tert-butoxycarbonyt-ethoxycarbonyimethyl-amino)-propionic acid TFA salt (197 mg, 0.714 mmol) in THF (10 ml) at room temperature is added EDCl (219 mg, 1.142 mmol) and HOBT (164 mg, 1.071 mmol). The mixture Is stirred at room temperature for 10 mins and then was added a solution of (R)-3-amino-4-(3'-chk>ro-biphenyl-4-yl)-bυtyrlc acid ethyl ester (202 mg, 0.571 mmol) in THF and TEA (0.199 ml, 1.428 mmol). The mixture is stirred at room temperature, Reverse phase HPLC [30 to 90% ACN-H2O (0.1%TFA) over 10 min by X-Bridge phenyl column] give the title compound (290 mg, 71% yield). LCMS (condition B): 575 (M+1); retention time ~ 1.52 min.
intermediate 54-2: 2>(tert-ButoxycarbonyI-ethoxycarbonyfmethyl>amtno)-propionic acid
Figure imgf000249_0001
To a solution of H-DL-Ala-OBzI. p~tosy!ate (2.88 g, 8.20 mmol) in THF (80 m!) at room temperature was added TEA (3.43 ml, 24.60 mmol) and followed by ethyl bromoacetate (1.096 ml, 9.84 mmof). The reaction was stirred at room temperature over night, There were some white solid in the reaction. The reaction mixture was filtered off the white solid and concentrated for purification. Flash chromatography (silica gel, 2 to 4% EtOH/DCM) gave the title compound as an oil (1.7 g, 78% yield), LCIvIS (condition B): 266 (M+1); retention time - 0,70 min.
Next, to a solution of 2-(ethoxycarbonylmethyl-amino)-propionic acid benzyl ester (1.7 g, 6.41 mmol) in DCM (80 ml) at 0 °C was added BOC-anhydride (2.232 ml, 9.61 mmol) and followed by TEA (2.68 ml, 19.22 mmol). The reaction mixture was slowly warmed up to room temperature and stirred over night. The reaction was quenched by brine and was extracted with DCM. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude. Flash chromatography (silica gel, 5 to 10% acetone/heptane) gave the title compound as an oii (1.66 g, 71% yield). LCMS (condition B): 366 (M+1); retention time = 1.13 min. Next, a solution of 2-(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-propionic acid benzyl ester in EtOAc was hydrogenated under H2 baioon by catalyst 10% Pd/C wet for 1 hr. The reaction was filtered off the catalyst and concentrated to give the crude for the next reaction.
Intermediate 55: (R)-3-Amino-4-(3'"Chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester trifluoroacetate
Figure imgf000250_0001
To a solution of (R)-3"tert-butoxycarbonylamino-4-(3'-chlorc~bipheny)-4-yl)-butyric acid ethyl ester (300 mg, 0.718 mmol) in THF (10 ml) at -78 °C is added LiHMDS/THF (1M) (1.579 ml, 1.579 mmol). The reaction mixture is stirred at -78 °C for 50 min and then to this mixture is added methyl iodine (0.054 ml, 0.861 mmoi) and the reaction is slowly warmed up to room temperature and stirred over night. The reaction is quenched by sat. NH4CI and is extracted with EtOAc. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude. Reverse phase HPLC [20 to 90% ACN-H2O (0.1%TFA) over 10 min by Sunfire C18] give (R)-3-tert-butoxycarbonylamino- 4-(3'~chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester. LCIvIS (condition B): 432 (M+1); retention time = 1.55 min. To a solution of (R)-3-tert-butoxycarbonylamino-4-(3'-chloro- biphenyl-4-yl)-2-methyl-butyric acid ethyl ester (240 mg, 0.556 mmol) in DCM (2 ml) at room temperature was added TFA (1.070 ml, 13,89 mmoi) and the mixture is stirred at room temperature, 1hr the reaction is done so the mixture is concentrated to give (R)-3-amino~4- (3'-chloro-biphenyl-4-yl)-2-methy!-butyric acid ethyl ester trifluoroacetate. LCMS (condition B): 332 (M+1); retention time = 1.00 min.
It can be seen that the compounds of the invention are useful as inhibitors of Neutral endopeptidase (EC 3.4.24.11) activity and therefore useful in the treatment of diseases and conditions associated with Neutral endopeptidase (EC 3.4.24.11) activity such as the diseases disclosed herein. It will be understood that the invention has been described by way of example only and modifications may be made whilst remaining within the scope and spirit of the invention.

Claims

1. A compound of Formula I':
Figure imgf000252_0001
Formula I'
or a pharmaceutically acceptable salt thereof, wherein:
R1 is H, C1-7alkyl, hydroxy, C1-7alkoxy. halogen, -SH, -S-C^alkyl or NRaRb;
R2 for each occurence, is independently C^alkyl, halo, NO2, CN, C1-7alkanoylamino, C3. rcycloalkyl, hydroxy, C1^aIkOXy1 haloC1-7alkyl, -NRaRb, C6.,oaryl, heteroaryl or heterocyclyl; wherein Ra and Rb for each occurrence are independently H or C1-7alkyl;
R3 is A1-C(0)X1 or A^R4;
R4 is Cβ-iσaryl or a heteroaryl, which can be monocyclic or bicyclic, and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, hydroxyC1-7aikyl, nitro, -NRaRb, -C(O)C1-7alkyl, C(O)-O-C 1 7aJky}, C1.
7alkoxy, halo, C1-7alkyl. halo-C1-7akyl, C2-7alkenyl, C^ioaryl, heteroaryl, ~NHSO2-C1-7alkyl and benzyl; or R4 is a heterocyclyl which can be optionally substituted with one or more substituents independently selected from the group consisting of oxo, hydroxy, hydroxyC^
7alkyl, amino, C(O)-O- C1-7alkyl, C1-7alkoxy, halo, d^alkyl, halo-C1-7akyl, Cβ-10aryl, heteroaryl,
-NHSOz-C^alkyl and benzyl;
Rs is H, halo, hydroxy, C1-7alkoxy. halo, C^alkyl or halo-d^akyl; and
X and X1 are independently OH, -O-C1-7alkyl, -NRaRb. -NHS(O)2-C1-7alkyl, -NHS(O)2-benzyl or -O- C6.ioaryl; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C6 ioaryl, heteroaryl, heterocydyl,
C(O)NH2, C(O)NH- C^alkyl, and C(O)N(C1-6alkyl)2;
B1 is -C(O)NH- or -NHC(O)-:
A1 is a bond or a linear or branched C^alkylene ; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C3./cycloalkyl, C1-7a!koxy, hydroxy and O-acetate; in which two geminai aikyt can optionally combine to form a C^ycydoalkyt; or
A1 is a linear or branched d^alkenylene; or
A1 is a linear CM alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O1 NRC; and A1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and C1-7alkyl; in which
Rc for each occurrence, is independently H, C^aikyl, -C(O)-O-C1-7alkyl or -CH2C(O)OH; or
A1 is a phenyl or a heteroaryl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of C^aikyl, C3.7cycloalkyf, halo-Crafkyl, hydroxy, C1-7alkoxy, halo, -NR8Rb, -OCH2COzH1 and -OCH2C(O)NH2; or
A1 is a C3-7CyClOaIkVl;
A1 ts -C1^alkylene-Cβ-io-aryl-, -C^alkylene-heteroaryl- or -C1^aikylene-beterocyclyl-, wherein
A1 may be in either direction; and
A3 is a bond or a linear or branched C1-7 alkylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-yalkoxy, hydroxy, O-Acetate and C3.7cycfoaikyl; n is 0, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocydyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocydyl is independently selected from O1 N and S.
2. A compound according to claim 1 of Formula I:
Figure imgf000253_0001
Formula or a pharmaceutically acceptable salt thereof, wherein:
R1 is H or Cv7aikyl;
R2 for each occurence, is independently C^alkyl, halo, NO?, CN, C,.?alkanoylamino, C3. rcycloalkyi, hydroxy, Cv7alkoxy, haloC^alkyl, -NRaRb, C^ioaryi, heteroaryt or heterocyclyl; wherein R8 and Rb for each occurrence are independently H or C^alkyl;
R3 is A1-C(O)X1 or A2-R4;
R4 is Cβ-ioaryi or a heteroaryl, which can be monocyclic or bicyclic, and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, hydroxyC-,.7alkyl, amino, C(O)-O- C1 ?alkyl, C^alkoxy, halo, C1-7alkyl, halo-C,-7akyl, Cβ-ioaryl, heteroaryl, -NHSO∑-C^alkyl and benzyl; or R4 is a heterocyclyl which can be optionally substituted with one or more substituents independently selected from the group consisting of oxo, hydroxy, hydroxyC1-7aJkyl, amino, C(O)-O- d,7alkyl, Cv/alkoxy, halo, d-ralkyl, halo-C1-7aky}, C6 10ary1, heteroaryl, -NHSO2-C1-7alkyl and benzyl;
Rs is H. halo, hydroxy, C1-7alkoxy, halo. Chalky! or hato-C1-7akyl; and
X and X1 are independently OH1 -O-Cvralkyt, NRaRb, or -O- C6.ioaryl; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ce.10aryl, heteroaryl, heterocyclyl, C(O)NH2. C(O)NH- Chalky!, and C(O)N(Cv θalkyl)2;
B1 is -C(O)NH- or -NHC(O)-;
A1 is a bond or a linear or branched C^alkylene ; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, G3.7cycloalkyi, C1-ralkoxy, hydroxy and O-acetate; in which two geminal alkyl can optionally combine to form a Ca^cycloalkyl; or
A1 is a phenyl or a heteroaryl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of C1-7alkyl, C^cycloalkyl, halo-C1-7alkyl, hydroxy, C1-7alkoxy, halo, -NRaRB, -OCHxCO7H1 and -OCH2C(O)NH2; or
A1 is a C3.7cyc!oalkyl;
A1 is -C1^alkytene-Cβ.rø-aryl-, -CMalkylene-heteroaryl- or -C^alkylene-heterocyclyl-, wherein
A1 may be in either direction; and
A2 is a bond or a linear or branched Cv7 aikylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-7alkoxy, hydroxy, O-Acetate and C3.rcydoalkyl, n is O, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyctic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyciyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryi or a heterocyciyl is independently selected from O, N and S.
3. The compound of Claim 1 or 2 wherein:
R1 is H or C1-ralkyl;
R2 for each occurrence, is independently Chalky!, halo, C3.?cycloalkyl, hydroxy, C1-7alkoxy, haloC1-7aikyl. -NRaRb, Cβ.2Caryl, heteroaryl or heterocyciyl; wherein Ra and Rb for each occurrence are independently H or d.yalkyl;
R3 ts A1-C(O)X1 or A2-R4;
R4 is C6-aoary} or a heteroaryl, each of which can be monocyclic or bicyclic and each of which can be optionaKy substituted with one or more substituents independently selected from the group consisting of hydroxy, C1-?alkoxy, halo, C1-7alkyl. halo-C^akyf, Cβ.ioaryl, heteroaryl, ■
NHSO2-C1- 7alkyl and benzyl;
Rδ is H; and
X and X1 are independently OH, -O-C1-7alkyl or NR8R";
B* is -C(O)NH- or -NHC(O)-;
A1 is a linear or branched C^alkylene ; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C3.7cycloalkyl, C1-
7alkoxy, hydroxy and O-acetate; in which two geminal alkyl can optionally combine to form a
Cs.rcycloalkyt; or
A1 is a phenyl or a heteroaryl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of C1,7alkyl, C3 /cycloalkyi, halo-Chalky!, hydroxy, C^alkoxy, halo, -NRV, -OCH2CO2H, and -OCH2C(O)NH2; and
A2 is a bond or a linear or branched C1-7 alkylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C^Talkoxy, hydroxy, O-Acetate and C3.7cyck>alkyl; and n Is 0, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyciyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S1 or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1, 2 or 3 having Formula Il or HA:
Figure imgf000256_0001
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1, 2 or 3 having formula III or IHA:
Figure imgf000256_0002
or a pharmaceutically acceptable salt thereof.
6. The compound of any of claims 1 to 5 wherein A1 is an optionally substituted linear or branched Ct.7 alkylene, or a pharmaceutically acceptable salt thereof.
7. The compounds of any of claims 1 to 6 wherein A1 is CH2CH2, or a pharmaceutically acceptable salt thereof.
8 The compound of any of claims 1 to 5 wherein A1 is an optionally substituted phenyl or heteroary!, or a pharmaceutically acceptable salt thereof
9 The compound of claim 1 , 2 or 3 having Formula VII or Vl)A
Figure imgf000257_0001
or a pharmaceutically acceptable salt thereof.
10 The compound of claim 9 wherein A2 is a bond or CH2 or CH2-CH2, or a pharmaceutically acceptable salt thereof.
11. The compound of any of claims 1 to 10 wherein R1 is H, R2 is independently halo, Ct-7alkoxy, hydroxy, C1-7alkyl or halo-Chalky! , n ts 0, 1 or 2 and X and X1 are independently OH or -O-C^alkyl, or a pharmaceutically acceptable salt thereof
12 The compounds of any of claims 1 to 11 wherein n is 1 or 2, R2 is meta-chloro or meta-fiuoro and the other optional R2 group is halo C1-7a)kyl, halo-C1-ralkyl, hydroxy and C1 7a(koxy. or a pharmaceutically acceptable salt thereof
13 A pharmaceutical composition compnsing a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers
14 A combination comprising- a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents selected from HMG-Co-A reductase inhibitor, an angiotensin receptor blocker, angiotensin converting enzyme Inhibitor, a calcium channel blocker, an endotheltn antagonist a renin inhibitor, a diuretic, an ApoA-l mimic, an anti-diabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, an aldosterone synthase inhibitors, a CETP inhibitor and a phosphodiesterase of type 5 (PDE5) inhibitor.
15. A method of inhibiting neutral endopeptidase EC. 3.4. 24.11, activity in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
16. The method according to claim 15, wherein the disorder or the disease is selected from hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, (eft ventricular hypertrophy, angina, renal insufficiency, renal failure, diabetic nephropathy, non- diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, sυpraventήcuiar and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis .atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD), pulmonary arterial hypertension, renal failure, cyclical oedema, Menieres disease, hyperaldosteroneism hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders, asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders, depression, psychotic condition, dementia, geriatric confusion, obesity and gastrointestinal disorders, wound healing, septic shock, gastric acid secretion dysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications, atherosclerosis, male and female sexual dysfunction.
17. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use as a medicament.
18. Use of the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for the treatment of a disorder or disease associated with neutral endopeptidase EC. 3.4. 24.11. activity in a subject in need of such treatment.
19. The use of ciaim 18, wherein the disorder or disease is selected from hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD), pulmonary arterial hypertension, renal failure, cyclical oedema, Menieres disease, hyperaidosteroneism hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders, asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders, depression, psychotic condition, dementia, geriatric confusion, obesity and gastrointestinal disorders, wound healing, septic shock, gastric acid secretion dysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications, atherosclerosis, male and female sexual dysfunction.
PCT/EP2010/057247 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors WO2010136493A1 (en)

Priority Applications (25)

Application Number Priority Date Filing Date Title
ES10720165.9T ES2523734T3 (en) 2009-05-28 2010-05-26 Aminopropionic derivatives substituted as neprilysin inhibitors
SI201030778T SI2435409T1 (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors
AU2010251967A AU2010251967B9 (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors
UAA201114061A UA106233C2 (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors
MX2011012628A MX2011012628A (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors.
CN201080032688.1A CN102574801B (en) 2009-05-28 2010-05-26 As the alanine derivatives of the replacement of enkephalinase inhibitor
EP10720165.9A EP2435409B1 (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors
JP2012512359A JP5420761B2 (en) 2009-05-28 2010-05-26 Substituted aminopropionic acid derivatives as neprilysin inhibitors
RS20140576A RS53664B1 (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors
BRPI1011657-5A BRPI1011657A2 (en) 2009-05-28 2010-05-26 substituted aminopropionic derivatives as neprilysin inhibitors
KR1020117031124A KR101442897B1 (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors
DK10720165.9T DK2435409T3 (en) 2009-05-28 2010-05-26 Substituted aminopropionic acid derivatives as neprilysin inhibitors
MEP-2014-140A ME01923B (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors
PL10720165T PL2435409T3 (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors
CA2763572A CA2763572C (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors
SG2011083094A SG176009A1 (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors
NZ596304A NZ596304A (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors
EA201101671A EA019511B1 (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors
ZA2011/08222A ZA201108222B (en) 2009-05-28 2011-11-09 Substituted aminopropionic derivatives as neprilysin inhibitors
IL216367A IL216367A0 (en) 2009-05-28 2011-11-14 Substituted aminopropionic derivatives as neprilysin inhibitors
TNP2011000592A TN2011000592A1 (en) 2009-05-28 2011-11-21 Substituted aminopropionic derivatives as neprilysin inhibitors
CU2011000217A CU24051B1 (en) 2009-05-28 2011-11-25 AMINO-PROPIONIC DERIVATIVES REPLACED AS NEPRILISINE INHIBITORS
MA34458A MA33636B1 (en) 2009-05-28 2011-12-16 SUBSTITUTED AMINOPROPIONIC DERIVATIVES AS INHIBITORS OF NEPRILYSINE
HRP20141050AT HRP20141050T1 (en) 2009-05-28 2014-10-30 Substituted aminopropionic derivatives as neprilysin inhibitors
SM201400175T SMT201400175B (en) 2009-05-28 2014-11-13 Aminopropionic derivatives substituted as neprilysin inhibitors

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US18175609P 2009-05-28 2009-05-28
US61/181,756 2009-05-28
US26314509P 2009-11-20 2009-11-20
US61/263,145 2009-11-20
US32494310P 2010-04-16 2010-04-16
US61/324,943 2010-04-16

Publications (1)

Publication Number Publication Date
WO2010136493A1 true WO2010136493A1 (en) 2010-12-02

Family

ID=42313042

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/057247 WO2010136493A1 (en) 2009-05-28 2010-05-26 Substituted aminopropionic derivatives as neprilysin inhibitors

Country Status (38)

Country Link
US (3) US8394853B2 (en)
EP (3) EP2435409B1 (en)
JP (1) JP5420761B2 (en)
KR (1) KR101442897B1 (en)
CN (2) CN102574801B (en)
AR (1) AR076707A1 (en)
AU (1) AU2010251967B9 (en)
BR (1) BRPI1011657A2 (en)
CA (1) CA2763572C (en)
CL (1) CL2011002990A1 (en)
CO (1) CO6470847A2 (en)
CR (1) CR20110616A (en)
CU (1) CU24051B1 (en)
DK (1) DK2435409T3 (en)
EA (1) EA019511B1 (en)
EC (1) ECSP11011560A (en)
ES (3) ES2523734T3 (en)
GT (1) GT201100303A (en)
HN (1) HN2011003097A (en)
HR (1) HRP20141050T1 (en)
IL (1) IL216367A0 (en)
JO (1) JO2962B1 (en)
MA (1) MA33636B1 (en)
ME (1) ME01923B (en)
MX (1) MX2011012628A (en)
MY (1) MY156270A (en)
NZ (1) NZ596304A (en)
PE (1) PE20120330A1 (en)
PL (1) PL2435409T3 (en)
PT (1) PT2435409E (en)
RS (1) RS53664B1 (en)
SG (1) SG176009A1 (en)
SI (1) SI2435409T1 (en)
SM (1) SMT201400175B (en)
TW (1) TWI445530B (en)
UY (1) UY32662A (en)
WO (1) WO2010136493A1 (en)
ZA (1) ZA201108222B (en)

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011092284A1 (en) * 2010-01-29 2011-08-04 Euroscreen S.A. Novel amino acid derivatives and their use as gpr43 receptor modulators
WO2011092187A1 (en) * 2010-01-26 2011-08-04 Sanofi Oxygen-substituted 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
WO2012065953A1 (en) * 2010-11-16 2012-05-24 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as nep inhibitors
WO2012082857A1 (en) * 2010-12-15 2012-06-21 Theravance, Inc. Neprilysin inhibitors
WO2012082853A1 (en) * 2010-12-15 2012-06-21 Theravance, Inc. Neprilysin inhibitors
US8222286B2 (en) 2009-11-20 2012-07-17 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US20120213806A1 (en) * 2011-02-17 2012-08-23 Theravance, Inc. Neprilysin inhibitors
US8263629B2 (en) 2009-05-28 2012-09-11 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
WO2012154249A1 (en) * 2011-02-17 2012-11-15 Theravance, Inc. Substituted aminobutyric derivatives as neprilysin inhibitors
US8394853B2 (en) 2009-05-28 2013-03-12 Novartis Ag Substituted aminopropionic derivatives as neprilysin inhibitors
WO2013014204A3 (en) * 2011-07-26 2013-04-04 Sanofi 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
WO2013113863A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113715A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113773A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113776A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113720A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113716A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113791A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013123222A1 (en) * 2012-02-15 2013-08-22 Theravance, Inc. Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compounds
CN103596928A (en) * 2011-05-31 2014-02-19 施万制药 Neprilysin inhibitors
WO2014053533A1 (en) * 2012-10-05 2014-04-10 Sanofi Use of substituted 3-heteroaroylamino-propionic acid derivatives as pharmaceuticals for prevention/treatment of atrial fibrillation
WO2014081702A2 (en) 2012-11-20 2014-05-30 Novartis Ag Synthetic linear apelin mimetics for the treatment of heart failure
WO2014126972A1 (en) * 2013-02-14 2014-08-21 Novartis Ag Substituted bisphenyl butanoic acid derivatives as nep inhibitors with improved in vivo efficacy
WO2014126979A1 (en) 2013-02-14 2014-08-21 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as nep (neutral endopeptidase) inhibitors
JP2014521626A (en) * 2011-07-26 2014-08-28 サノフイ Substituted 3- (thiazole-4-carbonyl)-or 3- (thiazole-2-carbonyl) -aminopropionic acid derivatives and their use as medicaments
WO2015013168A1 (en) 2013-07-25 2015-01-29 Novartis Ag Cyclic polypeptides for the treatment of heart failure
WO2015013169A2 (en) 2013-07-25 2015-01-29 Novartis Ag Bioconjugates of synthetic apelin polypeptides
CN104350042A (en) * 2012-06-08 2015-02-11 施万生物制药研发Ip有限责任公司 Neprilysin inhibitors
CN104350052A (en) * 2012-05-31 2015-02-11 施万生物制药研发Ip有限责任公司 Nitric oxide donor neprilysin inhibitors
JP2015505298A (en) * 2011-11-02 2015-02-19 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー Neprilysin inhibitor
US8993631B2 (en) 2010-11-16 2015-03-31 Novartis Ag Method of treating contrast-induced nephropathy
WO2015096651A1 (en) 2013-12-23 2015-07-02 Merck Sharp & Dohme Corp. Pyrimidone carboxamide compounds as pde2 inhibitors
WO2016116842A1 (en) 2015-01-23 2016-07-28 Novartis Ag Synthetic apelin fatty acid conjugates with improved half-life
WO2016149058A1 (en) 2015-03-17 2016-09-22 Merck Sharp & Dohme Corp. Triazolyl pyrimidinone compounds as pde2 inhibitors
WO2016154081A1 (en) 2015-03-26 2016-09-29 Merck Sharp & Dohme Corp. Pyrazolyl pyrimidinone compounds as pde2 inhibitors
JP2016185963A (en) * 2011-07-15 2016-10-27 ノバルティス アーゲー Aza bicyclic diaryl ether salt, method for manufacturing the same and method for manufacturing precursor thereof
WO2016209749A1 (en) 2015-06-25 2016-12-29 Merck Sharp & Dohme Corp. Substituted pyrazolo/imidazolo bicyclic compounds as pde2 inhibitors
WO2017108737A1 (en) 2015-12-23 2017-06-29 Chiesi Farmaceutici S.P.A. 1-(3-tert-butyl-phenyl)-3-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro- naphthalen-1-yl)-urea derivatives and their use as p38 mapk inhibitors
RU2632897C2 (en) * 2011-01-26 2017-10-11 Санофи Substituted derivatives of 3-heteroaroylaminopropionic acid and their application as drugs
CN107250119A (en) * 2015-02-19 2017-10-13 施万生物制药研发Ip有限责任公司 [(carbonyl of the 5 methyl oxazole 2) amino] valeric acid of (2R, 4R) 5 (base of 5 ' chlorine, 2 ' fluorine biphenyl 4) 2 hydroxyl 4
US10160762B2 (en) 2015-05-29 2018-12-25 Merck Sharp & Dohme Corp. 6-alkyl dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
US10174037B2 (en) 2015-06-04 2019-01-08 Merck Sharp & Dohme Corp. Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
US10195201B2 (en) 2015-05-05 2019-02-05 Merck Sharp & Dohme Corp. Heteroaryl-pyrimidinone compounds as PDE2 inhibitors
US10285989B2 (en) 2015-05-15 2019-05-14 Merck Sharp & Dohme Corp. Pyrimidinone amide compounds as PDE2 inhibitors
US10287293B2 (en) 2015-07-01 2019-05-14 Merck Sharp & Dohme Corp. Bicyclic heterocyclic compounds as PDE2 inhibitors
US10357481B2 (en) 2015-07-01 2019-07-23 Merck Sharp & Dohme Corp. Substituted triazolo bicyclic compounds as PDE2 inhibitors
US10668035B2 (en) 2018-02-07 2020-06-02 Novartis Ag Substituted bisphenyl butanoic ester derivatives as NEP inhibitors
WO2020110011A1 (en) 2018-11-27 2020-06-04 Novartis Ag Cyclic peptides as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders
WO2020110008A1 (en) 2018-11-27 2020-06-04 Novartis Ag Cyclic pentamer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorder
WO2020110009A1 (en) 2018-11-27 2020-06-04 Novartis Ag Cyclic tetramer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders
WO2023084449A1 (en) 2021-11-12 2023-05-19 Novartis Ag Diaminocyclopentylpyridine derivatives for the treatment of a disease or disorder

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8673974B2 (en) * 2010-11-16 2014-03-18 Novartis Ag Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors
EP2714648B1 (en) 2011-05-31 2017-08-16 Theravance Biopharma R&D IP, LLC Neprilysin inhibitors
EP2714660B1 (en) 2011-05-31 2018-09-26 Theravance Biopharma R&D IP, LLC Neprilysin inhibitors
US8822527B2 (en) 2011-10-17 2014-09-02 Biotheryx, Inc. Substituted biaryl alkyl amides
AR089954A1 (en) 2012-02-15 2014-10-01 Theravance Inc CRYSTALLINE FORM OF THE ESTER 5-METHYL-2-OXO- [1,3] DIOXOL-4-ILMETILIC ACID (2S, 4R) -5-BIFENIL-4-IL-2-HYDROXIMETHYL-2-METHYL-4 - [( 1H- [1,2,3] TRIAZOL-4-CARBONIL) AMINO] PENTANOIC
WO2013184898A1 (en) 2012-06-08 2013-12-12 Theravance, Inc. Neprilysin inhibitors
DK2882716T3 (en) 2012-08-08 2017-03-06 Theravance Biopharma R&D Ip Llc Neprilysin inhibitors
DK2964616T3 (en) 2013-03-05 2017-08-28 Theravance Biopharma R&D Ip Llc Neprilysin inhibitors
MX368011B (en) * 2013-09-17 2019-09-13 Vectus Biosystems Ltd Compositions for the treatment of hypertension and/or fibrosis.
CA2934898A1 (en) 2014-01-30 2015-08-06 Theravance Biopharma R&D Ip, Llc 5-biphenyl-4-heteroarylcarbonylamino-pentanoic acid derivatives as neprilysin inhibitors
US9593110B2 (en) * 2014-01-30 2017-03-14 Theravence Biopharma R&D IP, LLC Neprilysin inhibitors
WO2015189862A1 (en) * 2014-06-10 2015-12-17 Council Of Scientific & Industrial Research Chiral amines, a process for preparation and use thereof
WO2016086798A1 (en) * 2014-12-03 2016-06-09 上海翰森生物医药科技有限公司 Nep inhibitor crystalline free acid, calcium salt polymorph of same, preparation method for same, and applications thereof
CN104557600B (en) * 2015-01-26 2016-05-04 苏州明锐医药科技有限公司 Sha Ku is than bent preparation method
US9433598B2 (en) 2015-02-11 2016-09-06 Theravance Biopharma R&D Ip, Llc (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-(ethoxyoxalylamino)-2-hydroxymethyl-2-methylpentanoic acid
TW201632493A (en) * 2015-02-13 2016-09-16 諾華公司 New process
ES2933674T3 (en) * 2015-03-13 2023-02-13 Univ Indiana Res & Tech Corp PDE5 inhibitors for use in reducing renal cyst size and/or preventing renal cyst growth
ES2880123T3 (en) 2016-03-08 2021-11-23 Theravance Biopharma R&D Ip Llc Acid (25,4R) -5- (5'-chloro-2'-fluoro- [1,1'-biphenyl] -4-yl) -2- (ethoxymethyl) -4- (3-hydroxylisoxazole-5-carboxamido Crystalline) -2-methylpentanoic acid and uses thereof
CN106831473B (en) * 2017-02-22 2019-07-16 江西瑞雅药业有限公司 3- amide groups -4- (2 '-alkoxy -4- xenyl) butanoic acid derivative and preparation method thereof, pharmaceutical composition
FR3072379B1 (en) * 2017-10-18 2020-08-07 Pharmasynthese NEW DERIVATIVES OF STROMBIN AND THEIR USE IN COSMETICS
WO2019154665A1 (en) * 2018-02-07 2019-08-15 Basf Se New pyridine carboxamides
CN115806501A (en) * 2022-12-13 2023-03-17 中国药科大学 N-oxalyl-D-phenylalanine compounds and ester prodrugs thereof, preparation method, pharmaceutical composition and application

Citations (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2037754A (en) * 1978-11-25 1980-07-16 Nippon Kayaku Kk Threo - 3 -protected amino - 2 - hydroxy-4oxobutanoic acids or esters, their preparation and their use in the preparation of threo - 3 - amino - 2 - hydroxy-butanoylaminoacetic acids
EP0031058A1 (en) 1979-12-19 1981-07-01 Hoechst Aktiengesellschaft Sulfonyl ureas, processes for their preparation and pharmaceutical compositions containing these compounds
EP0039051A2 (en) 1980-04-24 1981-11-04 Merck & Co. Inc. Mannich-base hydroxamic acid prodrugs for the improved bioavailability of non-steroidal anti-inflammatory agents, a process for preparing and a pharmaceutical composition containing them
EP0122232A1 (en) 1983-04-13 1984-10-17 Ciba-Geigy Ag 20-Spiroxanes and analogues with open ring E, process for their preparation and pharmaceutical compositions
EP0147850A2 (en) 1983-12-30 1985-07-10 Dr. Karl Thomae GmbH Phenylacetic-acid derivatives, medicines containing these compounds and process for their preparation
EP0196222A2 (en) 1985-03-27 1986-10-01 Ajinomoto Co., Inc. Hypoglycemic agent
US4617307A (en) 1984-06-20 1986-10-14 Ciba-Geigy Corporation Substituted imidazo[1,5-A]pyridine derivatives as aromatase inhibitors
US4889861A (en) 1982-12-21 1989-12-26 Ciba-Geigy Corp. Substituted imidazo[1,5-a]pyridine derivatives and other substituted bicyclic derivatives and their use as aromatase inhibitors
WO1991011457A1 (en) 1990-01-24 1991-08-08 Buckley Douglas I Glp-1 analogs useful for diabetes treatment
JPH04149166A (en) * 1990-10-12 1992-05-22 Nippon Kayaku Co Ltd Novel keto acid amide derivative
US5118666A (en) 1986-05-05 1992-06-02 The General Hospital Corporation Insulinotropic hormone
US5120712A (en) 1986-05-05 1992-06-09 The General Hospital Corporation Insulinotropic hormone
EP0497192A2 (en) * 1991-02-01 1992-08-05 F. Hoffmann-La Roche Ag Amino acid derivatives
EP0507534A1 (en) 1991-03-30 1992-10-07 Kissei Pharmaceutical Co., Ltd. Succinic acid compounds
EP0526171A2 (en) 1991-07-30 1993-02-03 Ajinomoto Co., Inc. Crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine and methods for preparing them
EP0526708A1 (en) 1991-06-13 1993-02-10 F. Hoffmann-La Roche Ag Sulfonamide, preparation and use thereof as medicine and intermediate
EP0589874A1 (en) 1991-06-21 1994-04-06 Dr. Karl Thomae GmbH (s)(+)-2-ethoxy-4- n- 1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoic acid
WO1995015309A1 (en) 1993-12-03 1995-06-08 Ferring B.V. Dp-iv-serine protease inhibitors
US5512549A (en) 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
US5512548A (en) 1991-12-19 1996-04-30 Southwest Foundation For Biomedical Research CETP inhibitor polypeptide, antibodies against the synthetic polypeptide and prophylactic and therapeutic anti-atherosclerosis treatments
WO1996019459A1 (en) 1994-12-20 1996-06-27 F. Hoffmann-La Roche Ag Novel sulfonamides
DE19616486A1 (en) 1996-04-25 1997-10-30 Knoell Hans Forschung Ev Method of lowering blood glucose levels in mammals
US5705483A (en) 1993-12-09 1998-01-06 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
WO1998019998A2 (en) 1996-11-07 1998-05-14 Novartis Ag N-substituted 2-cyanopyrrolidines
WO2000017165A1 (en) 1998-09-17 2000-03-30 Pfizer Products Inc. 4-amino substituted-2-substituted-1,2,3,4-tetrahydroquinolines as cetp inhibitors
WO2000034241A1 (en) 1998-12-10 2000-06-15 Novartis Ag N-substituted 2-cyanopyrrolidines
US6197786B1 (en) 1998-09-17 2001-03-06 Pfizer Inc 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
WO2001076574A2 (en) 2000-04-12 2001-10-18 Novartis Ag Novel medical use of aldosterone synthase inhibitors alone or in combination with at1-receptor antagonists
WO2004014914A1 (en) 2002-08-07 2004-02-19 Novartis Ag Organic compounds as agents for the treatment of aldosterone mediated conditions
US6723752B2 (en) 1999-09-23 2004-04-20 Pharmacia Corporation (R)-chiral halogenated substituted n-benzyl-n-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
WO2004046145A1 (en) 2002-11-18 2004-06-03 Novartis Ag Imidazo[1, 5a]pyridine derivatives and methods for treating aldosterone mediated diseases
WO2004078163A2 (en) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
WO2005095409A2 (en) 2004-04-02 2005-10-13 Tanabe Seiyaku Co., Ltd. Tetrahydroquinoline derivatives and a process for preparing the same
WO2005097806A1 (en) 2004-03-26 2005-10-20 Eli Lilly And Company Compounds and methods for treating dyslipidemia
WO2006005726A2 (en) 2004-07-09 2006-01-19 Speedel Experimenta Ag Heterocyclic compounds
WO2006128852A2 (en) 2005-05-31 2006-12-07 Speedel Experimenta Ag Heterocyclic spiro-compounds as aldosterone synthase inhibitors
WO2006128853A1 (en) 2005-05-31 2006-12-07 Speedel Experimenta Ag Heterocyclic spiro-compounds as aldosterone synthase inhibitors
WO2006128851A1 (en) 2005-05-31 2006-12-07 Speedel Experimenta Ag Fused imidazole derivatives and use thereof as aldosterone synthase inhibitors
US20070049616A1 (en) 2005-08-25 2007-03-01 Ksander Gary M Organic compounds
WO2007065942A2 (en) 2005-12-09 2007-06-14 Speedel Experimenta Ag Bis-heterocyclic imidazolyl compounds
US20070208035A1 (en) 2004-05-28 2007-09-06 Honda Motor Co., Ltd. Heterocyclic compounds and their use as aldosterone synthase inhibitors
US20070225232A1 (en) 2004-05-28 2007-09-27 Peter Herold Tetrahydro-Imidazo [1,5-A] Pyridyin Derivatives as Aldosterone Synthase Inhibitors
WO2007116099A1 (en) 2006-04-12 2007-10-18 Speedel Experimenta Ag Imidazo compounds
WO2007116908A1 (en) 2006-04-04 2007-10-18 Taiyo Nippon Sanso Corporation Method for separation of methane, methane separator, and methane utilization system
EP1886695A1 (en) 2006-06-27 2008-02-13 Speedel Experimenta AG Pharmaceutical combination of an aldosterone synthase inhibitor and a glucocorticoid receptor antagonist or a cortisol synthesis inhibitor or a corticotropin releasing factor antagonist
WO2008027284A1 (en) 2006-08-25 2008-03-06 Novartis Ag Fused imidazole derivatives for the treatment of disorders mediated by aldosterone synthase and/or 11-beta-hydroxylase and/or aromatase
US20080076794A1 (en) 2004-05-28 2008-03-27 Peter Herold Heterocyclic Compounds And Their Use As Aldosterone Synthase Inhibitors
WO2008076862A2 (en) 2006-12-18 2008-06-26 Novartis Ag 1-substituted imidazole derivatives and their use as aldosterone synthase inhibitors
WO2008076860A1 (en) 2006-12-18 2008-06-26 Novartis Ag 4-imidazolyl-1,2,3,4-tetrahydroquinoline derivatives and their use as aldosterone/11-beta-hydroxylase inhibitors
WO2008076336A2 (en) 2006-12-18 2008-06-26 Novartis Ag Imidazoles as aldosterone synthase inhibitors
JP4149166B2 (en) 2002-01-08 2008-09-10 東京エレクトロン株式会社 Processing system and processing method
WO2008119744A1 (en) 2007-03-29 2008-10-09 Novartis Ag Heterocyclic spiro-compounds
US20090012068A1 (en) 2006-04-12 2009-01-08 Peter Herold Condensed Imidazole Derivatives as Aldosterone Synthase Inhibitors
US20100305145A1 (en) 2009-05-28 2010-12-02 Gary Mark Coppola Substituted Aminobutyric Derivatives as Neprilysin Inhibitors

Family Cites Families (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2074571B (en) 1980-04-11 1984-02-15 Wellcome Found Alpha-benzyl-substituted amides
US4610816A (en) 1980-12-18 1986-09-09 Schering Corporation Substituted dipeptides as inhibitors of enkephalinases
US4721726A (en) 1980-12-18 1988-01-26 Schering Corporation Substituted dipeptides as inhibitors of enkephalinases
JPS5865260A (en) 1981-10-13 1983-04-18 Microbial Chem Res Found 3-amino-2-hydroxy-4-phenylbutyric acid derivative and pharmaceutical composition
FR2518088B1 (en) 1981-12-16 1987-11-27 Roques Bernard NOVEL AMINO ACID DERIVATIVES AND THEIR THERAPEUTIC APPLICATION
EP0103077B1 (en) 1982-06-17 1988-05-18 Schering Corporation Substituted dipeptides, methods for their production, pharmaceutical compositions containing them, method for making such pharmaceutical compositions
AU569719B2 (en) 1983-01-28 1988-02-18 Schering Corporation Phosphorous compounds as inhibitors of enkephalinases
DE3467754D1 (en) 1983-10-03 1988-01-07 Squibb & Sons Inc ENKEPHALINASE INHIBITORS
CN1008092B (en) * 1983-10-03 1990-05-23 E·R·斯奎布父子公司 Process for preparation of enkephalinase inhibitors
JPS60248659A (en) 1984-05-25 1985-12-09 Microbial Chem Res Found 3(n-(mercaptoacyl))amino-4-arylbutyric acid derivative and analgesic containing said derivative as active component
US4743587A (en) 1985-09-10 1988-05-10 G. D. Searle & Co. Hydroxamic acid based collagenase inhibitors
FR2597865B1 (en) 1986-04-29 1990-11-09 Roussel Uclaf NOVEL DERIVATIVES OF A BENZYL ALKYL CARBOXYLIC ACID SUBSTITUTED BY A RADICAL 4-PYRIDINYL AMINOCARBONYL, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS
FR2605004B1 (en) 1986-09-25 1989-01-13 Centre Nat Rech Scient NOVEL AMINO ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION CONTAINING THEM
KR880007441A (en) * 1986-12-11 1988-08-27 알렌 제이.스피겔 Spiro-Substituted Glutaramide Diuretics
FR2609289B1 (en) 1987-01-06 1991-03-29 Bellon Labor Sa Roger NOVEL COMPOUNDS HAVING ACTIVITY OF COLLAGENASE INHIBITORS, PROCESS FOR PREPARING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
CA1337400C (en) 1987-06-08 1995-10-24 Norma G. Delaney Inhibitors of neutral endopeptidase
AU4211989A (en) 1988-08-18 1990-03-23 California Biotechnology, Inc. Atrial natriuretic peptide clearance inhibitors
FR2651229B1 (en) 1989-08-24 1991-12-13 Inst Nat Sante Rech Med NOVEL AMINO ACID DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION.
WO1991009840A1 (en) 1989-12-22 1991-07-11 Schering Corporation Mercaptocycloacyl aminoacid endopeptidase inhibitors
US5449682A (en) * 1990-02-13 1995-09-12 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted benzyl element
US5223516A (en) 1990-03-22 1993-06-29 E. R. Squibb & Sons, Inc. 3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides and method of using same
US5200426A (en) 1990-08-14 1993-04-06 Board Of Regents, The University Of Texas Inhibitors of neutral endopeptidase/CALLA as chemotherapeutic agents
US5294632A (en) 1991-05-01 1994-03-15 Ciba-Geigy Corporation Phosphono/biaryl substituted dipetide derivatives
GB9114006D0 (en) 1991-06-28 1991-08-14 Fujisawa Pharmaceutical Co New propionamide derivatives,processes for the preparation thereof and pharmaceutical composition comprising the same
EP0533130A1 (en) 1991-09-19 1993-03-24 Hoechst Aktiengesellschaft 2-Hydroxymethylpyridines, the corresponding pyridine-N-oxides and derivatives thereof, process for their preparation and their use
CA2078759C (en) 1991-09-27 2003-09-16 Alan M. Warshawsky Novel carboxyalkyl derivatives useful as inhibitors of enkephalinase and ace
US5250522A (en) 1992-10-09 1993-10-05 Ciba-Geigy Corporation Phosphono/biaryl substituted amino acid derivatives
US5273990A (en) 1992-09-03 1993-12-28 Ciba-Geigy Corporation Phosphono substituted tetrazole derivatives
US5217996A (en) * 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
JPH06234630A (en) 1992-12-17 1994-08-23 Tanabe Seiyaku Co Ltd Neutral metalloendopeptidase inhibitor
AU6267894A (en) 1993-03-02 1994-09-26 G.D. Searle & Co. N-acyl beta amino acid derivatives useful as platelet aggregation inhibitors
JP3576193B2 (en) 1993-12-03 2004-10-13 第一製薬株式会社 Biphenylmethyl-substituted valerylamide derivatives
US5517996A (en) 1994-04-21 1996-05-21 Hitachi Medical Corporation Ultrasonic diagnostic apparatus
IT1270261B (en) 1994-06-21 1997-04-29 Zambon Spa PEPTIDAL DERIVATIVES WITH INHIBITIVE ACTIVITY OF METALLOPEPTIDASES
DE69515465T2 (en) 1994-11-04 2000-08-03 Santen Pharmaceutical Co Ltd NEW HYDROXY-SUBSTITUTED 1,3-DIALKYL UREA DERIVATIVES
WO1996018606A1 (en) 1994-12-14 1996-06-20 Santen Pharmaceutical Co., Ltd. Novel 1,3-dialkylurea derivatives
FR2729668A1 (en) * 1995-01-23 1996-07-26 Adir NOVEL MERCAPTOALCANOYLDIPEPTIDES DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US5550119A (en) 1995-03-02 1996-08-27 Ciba-Geigy Corporation Phosphono substituted tetrazole derivatives as ECE inhibitors
US5710171A (en) 1995-05-24 1998-01-20 Merck & Co., Inc. Bisphenyl inhibitors of farnesyl-protein transferase
GB9609794D0 (en) * 1996-05-10 1996-07-17 Smithkline Beecham Plc Novel compounds
IL118657A0 (en) 1996-06-14 1996-10-16 Arad Dorit Inhibitors for picornavirus proteases
JP2002514179A (en) 1996-09-04 2002-05-14 ワーナー―ランバート・コンパニー Biphenylbutyric acid and its derivatives as inhibitors of matrix metalloproteinases
FR2755135B1 (en) 1996-10-25 2002-12-27 Inst Nat Sante Rech Med NOVEL (ALPHA-AMINOPHOSPHINO) PEPTIDES DERIVATIVES, PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM
ES2257808T3 (en) 1997-05-29 2006-08-01 MERCK &amp; CO., INC. (A NEW JERSEY CORP.) BIARILALCANOIC ACIDS AS CELLULAR ADHESION INHIBITORS.
HRP980443A2 (en) * 1997-08-18 1999-10-31 Carl P. Decicco Novel inhibitors of aggrecanase and matrix metalloproteinases for the treatment of arthritis
WO1999026923A1 (en) 1997-11-20 1999-06-03 Merck & Co., Inc. Para-aminomethylaryl carboxamide derivatives
WO1999026922A1 (en) 1997-11-21 1999-06-03 Merck & Co., Inc. Substituted pyrrole derivatives as cell adhesion inhibitors
WO1999026921A1 (en) 1997-11-24 1999-06-03 Merck & Co., Inc. SUBSTITUTED β-ALANINE DERIVATIVES AS CELL ADHESION INHIBITORS
MY153569A (en) 1998-01-20 2015-02-27 Mitsubishi Tanabe Pharma Corp Inhibitors of ?4 mediated cell adhesion
US6169103B1 (en) 1998-03-03 2001-01-02 Warner-Lambert Fluorine-substituted biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases
JP4070357B2 (en) 1999-06-03 2008-04-02 花王株式会社 Skin preparation
GB2354440A (en) 1999-07-20 2001-03-28 Merck & Co Inc Aryl amides as cell adhesion inhibitors
US6509330B2 (en) 2000-02-17 2003-01-21 Bristol-Myers Squibb Company Hydroxamic acid containing compounds useful as ACE inhibitors and/or NEP inhibotors
US7569724B2 (en) 2000-09-29 2009-08-04 Topotarget Uk Limited Carbamic acid compounds comprising an amide linkage as HDAC inhibitors
JP4820056B2 (en) 2002-01-17 2011-11-24 ノバルティス アーゲー Pharmaceutical composition comprising valsartan and NEP inhibitor
JP4233353B2 (en) 2002-02-27 2009-03-04 田辺三菱製薬株式会社 Pharmaceutical composition
US20040063761A1 (en) 2002-08-06 2004-04-01 Kuduk Scott D. 2-(biarylalkyl)amino-3-(fluoroalkanoylamino)pyridine derivatives
US20040142379A1 (en) 2003-01-16 2004-07-22 Carlsberg Research Laboratory Affinity fishing for ligands and proteins receptors
EP1622886A2 (en) 2003-04-30 2006-02-08 The Institutes for Pharmaceutical Discovery, LLC Substituted amino carboxylic acids as inhibitors of protein tyrosine phosphatase-1b
CN1566065A (en) * 2003-06-27 2005-01-19 中国医学科学院药物研究所 Alpha position heteroatom substituted gamma aryl ketobutyric acid derivative, process, pharmaceutical combination and uses thereof
WO2005012270A2 (en) 2003-07-29 2005-02-10 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic amines, amides, and sulfur-containing compounds and methods of making and using the same
US7459472B2 (en) 2003-08-08 2008-12-02 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use
US20070265345A1 (en) 2004-07-27 2007-11-15 Smithkline Beecham Corporation Novel Biphenyl Compounds And Their Use
WO2006055725A2 (en) 2004-11-18 2006-05-26 The Institutes For Pharmaceutical Discovery, Llc Substituted amino acids as protein tyrosine phosphatase inhibitors
WO2006069096A1 (en) 2004-12-20 2006-06-29 Pharmacyclics, Inc. Silanol derivatives as inhibitors of histone deacetylase
MY146830A (en) 2005-02-11 2012-09-28 Novartis Ag Combination of organic compounds
CA2600570C (en) * 2005-03-14 2011-12-06 Transtech Pharma, Inc. Benzazole derivatives, compositions, and methods of use as .beta.-secretase inhibitors
WO2007045663A2 (en) 2005-10-19 2007-04-26 Novartis Ag Combination of an ati receptor antagonist and a np inhibitor fro treating ia hypertension and heartfailure
RU2008122712A (en) 2005-11-08 2009-12-20 Новартис АГ (CH) COMBINATION OF ORGANIC COMPOUNDS
AR057882A1 (en) 2005-11-09 2007-12-26 Novartis Ag DOUBLE ACTION COMPOUNDS OF ANGIOTENSIN RECEPTOR BLOCKERS AND NEUTRAL ENDOPEPTIDASE INHIBITORS
CN101443007A (en) 2006-05-15 2009-05-27 Irm责任有限公司 TEREPHTHALAMATE compounds and compositions, and their use as HIV integrase inhibitors
EP1903027A1 (en) 2006-09-13 2008-03-26 Novartis AG Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors
AU2008204546B2 (en) 2007-01-12 2012-03-15 Novartis Ag Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid
TW200838501A (en) 2007-02-02 2008-10-01 Theravance Inc Dual-acting antihypertensive agents
TWI448284B (en) 2007-04-24 2014-08-11 Theravance Inc Dual-acting antihypertensive agents
US8980833B2 (en) 2007-05-10 2015-03-17 R&D-Biopharmaceuticals Gmbh Tubulysine derivatives
TWI406850B (en) 2007-06-05 2013-09-01 Theravance Inc Dual-acting benzoimidazole antihypertensive agents
US7834041B2 (en) * 2007-09-07 2010-11-16 Theravance, Inc. Dual-acting antihypertensive agents
IL262990B2 (en) 2007-11-06 2023-10-01 Novartis Ag Dual-acting pharmaceutical compositions based on superstructures of angiotensin receptor antagonist/blocker (arb) and neutral endopeptidase (nep) inhibitor
EP2225210B1 (en) 2007-12-11 2012-04-25 Theravance, Inc. Dual-acting benzoimidazole derivative and their use as antihypertensive agents
EP2070928A1 (en) 2007-12-12 2009-06-17 NERVIANO MEDICAL SCIENCES S.r.l. 7-azaindol-3-ylacrylamides active as kinase inhibitors
PE20091364A1 (en) 2008-01-17 2009-10-13 Novartis Ag PROCESS FOR THE PREPARATION OF NEP INHIBITORS
WO2010011821A2 (en) 2008-07-24 2010-01-28 Theravance, Inc. Dual-acting antihypertensive agents
WO2011035569A1 (en) 2009-09-23 2011-03-31 Zhejiang Jiuzhou Pharmaceutical Co., Ltd. Process for manufacture of n-acylbphenyl alanine
BRPI1011657A2 (en) 2009-05-28 2019-04-16 Novartis Ag substituted aminopropionic derivatives as neprilysin inhibitors
JO2967B1 (en) 2009-11-20 2016-03-15 نوفارتس ايه جي Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors

Patent Citations (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2037754A (en) * 1978-11-25 1980-07-16 Nippon Kayaku Kk Threo - 3 -protected amino - 2 - hydroxy-4oxobutanoic acids or esters, their preparation and their use in the preparation of threo - 3 - amino - 2 - hydroxy-butanoylaminoacetic acids
EP0031058A1 (en) 1979-12-19 1981-07-01 Hoechst Aktiengesellschaft Sulfonyl ureas, processes for their preparation and pharmaceutical compositions containing these compounds
EP0039051A2 (en) 1980-04-24 1981-11-04 Merck & Co. Inc. Mannich-base hydroxamic acid prodrugs for the improved bioavailability of non-steroidal anti-inflammatory agents, a process for preparing and a pharmaceutical composition containing them
US4889861A (en) 1982-12-21 1989-12-26 Ciba-Geigy Corp. Substituted imidazo[1,5-a]pyridine derivatives and other substituted bicyclic derivatives and their use as aromatase inhibitors
EP0122232A1 (en) 1983-04-13 1984-10-17 Ciba-Geigy Ag 20-Spiroxanes and analogues with open ring E, process for their preparation and pharmaceutical compositions
EP0147850A2 (en) 1983-12-30 1985-07-10 Dr. Karl Thomae GmbH Phenylacetic-acid derivatives, medicines containing these compounds and process for their preparation
EP0207331A1 (en) 1983-12-30 1987-01-07 Dr. Karl Thomae GmbH Solid forms of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-amino-carbonylmethyl]-benzoic acid, medicaments containing these forms and process for their preparation
US4617307A (en) 1984-06-20 1986-10-14 Ciba-Geigy Corporation Substituted imidazo[1,5-A]pyridine derivatives as aromatase inhibitors
EP0196222A2 (en) 1985-03-27 1986-10-01 Ajinomoto Co., Inc. Hypoglycemic agent
US5120712A (en) 1986-05-05 1992-06-09 The General Hospital Corporation Insulinotropic hormone
US5118666A (en) 1986-05-05 1992-06-02 The General Hospital Corporation Insulinotropic hormone
WO1991011457A1 (en) 1990-01-24 1991-08-08 Buckley Douglas I Glp-1 analogs useful for diabetes treatment
JPH04149166A (en) * 1990-10-12 1992-05-22 Nippon Kayaku Co Ltd Novel keto acid amide derivative
EP0497192A2 (en) * 1991-02-01 1992-08-05 F. Hoffmann-La Roche Ag Amino acid derivatives
EP0507534A1 (en) 1991-03-30 1992-10-07 Kissei Pharmaceutical Co., Ltd. Succinic acid compounds
EP0526708A1 (en) 1991-06-13 1993-02-10 F. Hoffmann-La Roche Ag Sulfonamide, preparation and use thereof as medicine and intermediate
EP0589874A1 (en) 1991-06-21 1994-04-06 Dr. Karl Thomae GmbH (s)(+)-2-ethoxy-4- n- 1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoic acid
EP0526171A2 (en) 1991-07-30 1993-02-03 Ajinomoto Co., Inc. Crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine and methods for preparing them
US5512548A (en) 1991-12-19 1996-04-30 Southwest Foundation For Biomedical Research CETP inhibitor polypeptide, antibodies against the synthetic polypeptide and prophylactic and therapeutic anti-atherosclerosis treatments
WO1995015309A1 (en) 1993-12-03 1995-06-08 Ferring B.V. Dp-iv-serine protease inhibitors
US5705483A (en) 1993-12-09 1998-01-06 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
US5512549A (en) 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
WO1996019459A1 (en) 1994-12-20 1996-06-27 F. Hoffmann-La Roche Ag Novel sulfonamides
DE19616486A1 (en) 1996-04-25 1997-10-30 Knoell Hans Forschung Ev Method of lowering blood glucose levels in mammals
WO1998019998A2 (en) 1996-11-07 1998-05-14 Novartis Ag N-substituted 2-cyanopyrrolidines
US6197786B1 (en) 1998-09-17 2001-03-06 Pfizer Inc 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
US6140343A (en) 1998-09-17 2000-10-31 Pfizer 4-amino substituted-2-substituted-1,2,3,4-tetrahydroquinolines
WO2000017165A1 (en) 1998-09-17 2000-03-30 Pfizer Products Inc. 4-amino substituted-2-substituted-1,2,3,4-tetrahydroquinolines as cetp inhibitors
WO2000034241A1 (en) 1998-12-10 2000-06-15 Novartis Ag N-substituted 2-cyanopyrrolidines
US6723752B2 (en) 1999-09-23 2004-04-20 Pharmacia Corporation (R)-chiral halogenated substituted n-benzyl-n-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
WO2001076574A2 (en) 2000-04-12 2001-10-18 Novartis Ag Novel medical use of aldosterone synthase inhibitors alone or in combination with at1-receptor antagonists
JP4149166B2 (en) 2002-01-08 2008-09-10 東京エレクトロン株式会社 Processing system and processing method
WO2004014914A1 (en) 2002-08-07 2004-02-19 Novartis Ag Organic compounds as agents for the treatment of aldosterone mediated conditions
WO2004046145A1 (en) 2002-11-18 2004-06-03 Novartis Ag Imidazo[1, 5a]pyridine derivatives and methods for treating aldosterone mediated diseases
WO2004078163A2 (en) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
WO2005097806A1 (en) 2004-03-26 2005-10-20 Eli Lilly And Company Compounds and methods for treating dyslipidemia
WO2005095409A2 (en) 2004-04-02 2005-10-13 Tanabe Seiyaku Co., Ltd. Tetrahydroquinoline derivatives and a process for preparing the same
US20070208035A1 (en) 2004-05-28 2007-09-06 Honda Motor Co., Ltd. Heterocyclic compounds and their use as aldosterone synthase inhibitors
US20080076794A1 (en) 2004-05-28 2008-03-27 Peter Herold Heterocyclic Compounds And Their Use As Aldosterone Synthase Inhibitors
US20080318978A2 (en) 2004-05-28 2008-12-25 Speedel Experimenta Ag Heterocyclic compounds and their use as aldosterone synthase inhibitors
US20070225232A1 (en) 2004-05-28 2007-09-27 Peter Herold Tetrahydro-Imidazo [1,5-A] Pyridyin Derivatives as Aldosterone Synthase Inhibitors
WO2006005726A2 (en) 2004-07-09 2006-01-19 Speedel Experimenta Ag Heterocyclic compounds
WO2006128851A1 (en) 2005-05-31 2006-12-07 Speedel Experimenta Ag Fused imidazole derivatives and use thereof as aldosterone synthase inhibitors
WO2006128852A2 (en) 2005-05-31 2006-12-07 Speedel Experimenta Ag Heterocyclic spiro-compounds as aldosterone synthase inhibitors
WO2006128853A1 (en) 2005-05-31 2006-12-07 Speedel Experimenta Ag Heterocyclic spiro-compounds as aldosterone synthase inhibitors
US20070049616A1 (en) 2005-08-25 2007-03-01 Ksander Gary M Organic compounds
WO2007065942A2 (en) 2005-12-09 2007-06-14 Speedel Experimenta Ag Bis-heterocyclic imidazolyl compounds
WO2007116908A1 (en) 2006-04-04 2007-10-18 Taiyo Nippon Sanso Corporation Method for separation of methane, methane separator, and methane utilization system
WO2007116099A1 (en) 2006-04-12 2007-10-18 Speedel Experimenta Ag Imidazo compounds
US20090048241A1 (en) 2006-04-12 2009-02-19 Speedel Experimenta Ag Condensed Imidazole Derivatives as Aromatase Inhibitors
US20090012068A1 (en) 2006-04-12 2009-01-08 Peter Herold Condensed Imidazole Derivatives as Aldosterone Synthase Inhibitors
EP1886695A1 (en) 2006-06-27 2008-02-13 Speedel Experimenta AG Pharmaceutical combination of an aldosterone synthase inhibitor and a glucocorticoid receptor antagonist or a cortisol synthesis inhibitor or a corticotropin releasing factor antagonist
WO2008027284A1 (en) 2006-08-25 2008-03-06 Novartis Ag Fused imidazole derivatives for the treatment of disorders mediated by aldosterone synthase and/or 11-beta-hydroxylase and/or aromatase
WO2008076862A2 (en) 2006-12-18 2008-06-26 Novartis Ag 1-substituted imidazole derivatives and their use as aldosterone synthase inhibitors
WO2008076336A2 (en) 2006-12-18 2008-06-26 Novartis Ag Imidazoles as aldosterone synthase inhibitors
WO2008076860A1 (en) 2006-12-18 2008-06-26 Novartis Ag 4-imidazolyl-1,2,3,4-tetrahydroquinoline derivatives and their use as aldosterone/11-beta-hydroxylase inhibitors
WO2008119744A1 (en) 2007-03-29 2008-10-09 Novartis Ag Heterocyclic spiro-compounds
US20100305145A1 (en) 2009-05-28 2010-12-02 Gary Mark Coppola Substituted Aminobutyric Derivatives as Neprilysin Inhibitors

Non-Patent Citations (31)

* Cited by examiner, † Cited by third party
Title
"Enantioselective synthesis of (3-amino acids, 2nd Edition", 2005, JOHN WILEY AND SONS, INC.
"Enantioselective synthesis of beta-amino acids, 2nd Edition", 2005, JOHN WILEY AND SONS, INC.
"Remington's Pharmaceutical Sciences, 18th Ed.", 1990, MACK PRINTING COMPANY, pages: 1289 - 1329
"Remington's Pharmaceutical Sciences, 20th ed.,", 1985, MACK PUBLISHING COMPANY
BIOORG. MED. CHEM. LETT., vol. 6, 1996, pages 1951 - 1954
BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 12, 2002, pages 101 - 104
BUNDGAARD, J. MED. CHEM., 1989, pages 2503
BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
C. ORSKOV ET AL., J. BIOL. CHEM., vol. 264, 1989, pages 12826
DATABASE WPI Week 199227, Derwent World Patents Index; AN 1992-223453, XP002591646 *
DOERING K; MEDER G; HINNENBERGER M; WOELCKE J; MAYR LM, HASSIEPEN U BIOMOL SCREEN, vol. 14, no. 1, January 2009 (2009-01-01), pages 1 - 9
GREIG ET AL., DIABETOLOGIA, vol. 42, 1999, pages 45 - 50
HOUBEN-WEYL: "Methods of Organic Synthesis,4th Ed.", vol. 21, 1952, THIEME
J CLIN PHARMACOL, vol. 27, 1987, pages 927
J HYPERTENS, vol. 19, 2001, pages 1923
J. ANTIBIOT., vol. 49, no. 8, 1996, pages 815 - 816
J. F. W. MCOMIE: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
J. ORG. CHEM., vol. 67, 2002, pages 1102 - 1108
J.MED.CHEM., vol. 29, 1986, pages 538 - 549
JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, 1998, pages 1513
ORGANIC LETTERS, vol. 4, no. 22, 2002, pages 3803 - 3805
PEPTIDES, vol. 9, 1988, pages 173
PHARMACOL REV, vol. 45, 1993, pages 87
STAHL; WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
SYNLETT, vol. 4, 2006, pages 539 - 542
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Synthesis, Third edition", 1999, WILEY
TETRAHEDRON LETTERS, vol. 49, no. 33, 2008, pages 4977 - 4980
TETRAHEDRON: ASYMMETRY, vol. 17, no. 2, 2006, pages 205 - 209
W. YAO ET AL: "Potent P1' biphenylmethyl substituted aggrecanase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 12, 2002, Pergamon, Elsevier Science, pages 101 - 104, XP002591647, ISSN: 0960-894X *
W.E. SCHMIDT ET AL., DIABETOLOGIA, vol. 28, 1985, pages 704 - 707
WERMUTH: "The Practice of Medicinal Chemistry", 2001, ACADEMIC PRESS, article "Ch. 31-32"

Cited By (117)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9603819B2 (en) 2009-05-28 2017-03-28 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
US8263629B2 (en) 2009-05-28 2012-09-11 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
US8394853B2 (en) 2009-05-28 2013-03-12 Novartis Ag Substituted aminopropionic derivatives as neprilysin inhibitors
US9006249B2 (en) 2009-05-28 2015-04-14 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
US8877786B2 (en) 2009-11-20 2014-11-04 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8222286B2 (en) 2009-11-20 2012-07-17 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
AU2010320930B2 (en) * 2009-11-20 2014-05-15 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8377978B2 (en) 2009-11-20 2013-02-19 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8642635B2 (en) 2009-11-20 2014-02-04 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
WO2011092187A1 (en) * 2010-01-26 2011-08-04 Sanofi Oxygen-substituted 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
US8664257B2 (en) 2010-01-26 2014-03-04 Sanofi Oxygen-substituted 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
WO2011092284A1 (en) * 2010-01-29 2011-08-04 Euroscreen S.A. Novel amino acid derivatives and their use as gpr43 receptor modulators
US8877815B2 (en) 2010-11-16 2014-11-04 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as NEP
WO2012065953A1 (en) * 2010-11-16 2012-05-24 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as nep inhibitors
US8993631B2 (en) 2010-11-16 2015-03-31 Novartis Ag Method of treating contrast-induced nephropathy
CN103261168A (en) * 2010-12-15 2013-08-21 施万制药 Neprilysin inhibitors
WO2012082853A1 (en) * 2010-12-15 2012-06-21 Theravance, Inc. Neprilysin inhibitors
KR101892500B1 (en) 2010-12-15 2018-08-28 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 Neprilysin inhibitors
KR101892611B1 (en) 2010-12-15 2018-08-28 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 Neprilysin inhibitors
WO2012082857A1 (en) * 2010-12-15 2012-06-21 Theravance, Inc. Neprilysin inhibitors
CN105061314A (en) * 2010-12-15 2015-11-18 施万生物制药研发Ip有限责任公司 Neprilysin inhibitors
KR20140027918A (en) * 2010-12-15 2014-03-07 세라밴스 인코포레이티드 Neprilysin inhibitors
AU2011343903A1 (en) * 2010-12-15 2013-07-18 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
CN103261164A (en) * 2010-12-15 2013-08-21 施万制药 Neprilysin inhibitors
KR20140036134A (en) * 2010-12-15 2014-03-25 세라밴스 인코포레이티드 Neprilysin inhibitors
RU2622288C2 (en) * 2010-12-15 2017-06-14 ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи,ЭлЭлСи Inhibitors of nonprilyzine
AU2011343899B2 (en) * 2010-12-15 2016-06-30 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
JP2013545811A (en) * 2010-12-15 2013-12-26 セラヴァンス， インコーポレーテッド Neprilysin inhibitor
AU2011343899A1 (en) * 2010-12-15 2013-06-06 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
JP2014503534A (en) * 2010-12-15 2014-02-13 セラヴァンス， インコーポレーテッド Neprilysin inhibitor
AU2011343903B2 (en) * 2010-12-15 2016-06-30 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
US11851443B2 (en) 2010-12-15 2023-12-26 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
RU2605557C2 (en) * 2010-12-15 2016-12-20 ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи,ЭлЭлСи Neprilysin inhibitors
RU2632897C2 (en) * 2011-01-26 2017-10-11 Санофи Substituted derivatives of 3-heteroaroylaminopropionic acid and their application as drugs
JP2014505734A (en) * 2011-02-17 2014-03-06 セラヴァンス， インコーポレーテッド Substituted aminobutyric acid derivatives as neprilysin inhibitors
US20120213806A1 (en) * 2011-02-17 2012-08-23 Theravance, Inc. Neprilysin inhibitors
JP2014508755A (en) * 2011-02-17 2014-04-10 セラヴァンス， インコーポレーテッド Substituted aminobutyric acid derivatives as neprilysin inhibitors
WO2012112742A1 (en) * 2011-02-17 2012-08-23 Theravance, Inc. Substituted aminobutyric derivatives as neprilysin inhibitors
KR101854874B1 (en) 2011-02-17 2018-05-04 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 Substituted aminobutyric derivatives as neprilysin inhibitors
CN103380119B (en) * 2011-02-17 2016-02-17 施万生物制药研发Ip有限责任公司 As the amino butyric acid derivative be substituted of enkephalinase inhibitor
AU2012217615B2 (en) * 2011-02-17 2016-09-29 Theravance Biopharma R&D Ip, Llc Substituted aminobutyric derivatives as neprilysin inhibitors
TWI548622B (en) * 2011-02-17 2016-09-11 施萬生物製藥研發Ｉｐ有限責任公司 Neprilysin inhibitors
US8481044B2 (en) * 2011-02-17 2013-07-09 Theravance, Inc. Neprilysin inhibitors
CN103380119A (en) * 2011-02-17 2013-10-30 施万制药 Substituted aminobutyric derivatives as neprilysin inhibitors
WO2012154249A1 (en) * 2011-02-17 2012-11-15 Theravance, Inc. Substituted aminobutyric derivatives as neprilysin inhibitors
CN103596928A (en) * 2011-05-31 2014-02-19 施万制药 Neprilysin inhibitors
JP2016185963A (en) * 2011-07-15 2016-10-27 ノバルティス アーゲー Aza bicyclic diaryl ether salt, method for manufacturing the same and method for manufacturing precursor thereof
US9802931B2 (en) 2011-07-15 2017-10-31 Novartis Ag Salts of aza-bicyclic di-aryl ethers and methods to make them or their precursors
US10421755B2 (en) 2011-07-15 2019-09-24 Novartis Ag Salts of aza-bicyclic di-aryl ethers and methods to make them or their precursors
US9751858B2 (en) 2011-07-26 2017-09-05 Sanofi 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
WO2013014204A3 (en) * 2011-07-26 2013-04-04 Sanofi 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
US9353068B2 (en) 2011-07-26 2016-05-31 Sanofi 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
CN105646362B (en) * 2011-07-26 2019-07-05 赛诺菲 3- heteroaroylamino-propanoic derivatives and its purposes as drug
JP2014521626A (en) * 2011-07-26 2014-08-28 サノフイ Substituted 3- (thiazole-4-carbonyl)-or 3- (thiazole-2-carbonyl) -aminopropionic acid derivatives and their use as medicaments
EP3037417A3 (en) * 2011-07-26 2016-10-12 Sanofi 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
CN105646362A (en) * 2011-07-26 2016-06-08 赛诺菲 3-heteroaroylamino-propionic acid derivatives and their use as medicine
CN103827097A (en) * 2011-07-26 2014-05-28 赛诺菲 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
JP2015505298A (en) * 2011-11-02 2015-02-19 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー Neprilysin inhibitor
WO2013113776A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113791A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113716A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113720A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113773A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113715A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113863A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013123222A1 (en) * 2012-02-15 2013-08-22 Theravance, Inc. Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compounds
US9676742B2 (en) 2012-02-15 2017-06-13 Theravance Biopharma R&D Ip, Llc Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compound
CN104125952A (en) * 2012-02-15 2014-10-29 施万生物制药研发Ip有限责任公司 Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compounds
US8962864B2 (en) 2012-02-15 2015-02-24 Theravance Biopharma R&D Ip, Llc Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compounds
US10011581B2 (en) 2012-02-15 2018-07-03 Theravance Biopharma R&D Ip, Llc Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compound
CN104125952B (en) * 2012-02-15 2016-06-29 施万生物制药研发Ip有限责任公司 The method preparing 4-amino-5-biphenyl-4-base-2-methylol-2-methvl-pentanoic acid compound
US9096577B2 (en) 2012-02-15 2015-08-04 Theravance Biopharma R&D Ip, Llc Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compound
JP2015523980A (en) * 2012-05-31 2015-08-20 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー Neprilysin inhibitor, a nitric oxide donor
CN104350052A (en) * 2012-05-31 2015-02-11 施万生物制药研发Ip有限责任公司 Nitric oxide donor neprilysin inhibitors
CN104350052B (en) * 2012-05-31 2017-05-31 施万生物制药研发Ip有限责任公司 Nitric oxide donors enkephalinase inhibitor
JP2015525215A (en) * 2012-06-08 2015-09-03 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー Neprilysin inhibitor
CN104350042A (en) * 2012-06-08 2015-02-11 施万生物制药研发Ip有限责任公司 Neprilysin inhibitors
CN104350042B (en) * 2012-06-08 2017-05-24 施万生物制药研发Ip有限责任公司 Neprilysin inhibitors
WO2014053533A1 (en) * 2012-10-05 2014-04-10 Sanofi Use of substituted 3-heteroaroylamino-propionic acid derivatives as pharmaceuticals for prevention/treatment of atrial fibrillation
WO2014081702A2 (en) 2012-11-20 2014-05-30 Novartis Ag Synthetic linear apelin mimetics for the treatment of heart failure
WO2014126972A1 (en) * 2013-02-14 2014-08-21 Novartis Ag Substituted bisphenyl butanoic acid derivatives as nep inhibitors with improved in vivo efficacy
US10112963B2 (en) 2013-02-14 2018-10-30 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
US9480693B2 (en) 2013-02-14 2016-11-01 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
TWI636057B (en) * 2013-02-14 2018-09-21 瑞士商諾華公司 Substituted bisphenyl butanoic phosphonic acid derivatives as nep inhibitors
AU2014216424B2 (en) * 2013-02-14 2016-05-05 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP (neutral endopeptidase) inhibitors
EA026989B1 (en) * 2013-02-14 2017-06-30 Новартис Аг Substituted bisphenyl butanoic acid derivatives as nep inhibitors with improved in vivo efficacy
US9163040B2 (en) 2013-02-14 2015-10-20 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
EA028583B1 (en) * 2013-02-14 2017-12-29 Новартис Аг Substituted bisphenyl butanoic phosphonic acid derivatives as nep (neutral endopeptidase) inhibitors
WO2014126979A1 (en) 2013-02-14 2014-08-21 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as nep (neutral endopeptidase) inhibitors
AU2014216417B2 (en) * 2013-02-14 2016-05-12 Novartis Ag Substituted bisphenyl butanoic acid derivatives as NEP inhibitors with improved in vivo efficacy
US9102635B2 (en) 2013-02-14 2015-08-11 Novartis Ag Substituted bisphenyl butanoic acid derivatives as NEP inhibitors with improved in vivo efficacy
WO2015013168A1 (en) 2013-07-25 2015-01-29 Novartis Ag Cyclic polypeptides for the treatment of heart failure
WO2015013169A2 (en) 2013-07-25 2015-01-29 Novartis Ag Bioconjugates of synthetic apelin polypeptides
WO2015096651A1 (en) 2013-12-23 2015-07-02 Merck Sharp & Dohme Corp. Pyrimidone carboxamide compounds as pde2 inhibitors
US9815796B2 (en) 2013-12-23 2017-11-14 Merck Sharp & Dohme Corp. Pyrimidone carboxamide compounds as PDE2 inhibitors
WO2016116842A1 (en) 2015-01-23 2016-07-28 Novartis Ag Synthetic apelin fatty acid conjugates with improved half-life
CN107250119A (en) * 2015-02-19 2017-10-13 施万生物制药研发Ip有限责任公司 [(carbonyl of the 5 methyl oxazole 2) amino] valeric acid of (2R, 4R) 5 (base of 5 ' chlorine, 2 ' fluorine biphenyl 4) 2 hydroxyl 4
CN107250119B (en) * 2015-02-19 2020-09-22 施万生物制药研发Ip有限责任公司 (2R,4R) -5- (5 '-chloro-2' -fluorobiphenyl-4-yl) -2-hydroxy-4- [ (5-methyloxazole-2-carbonyl) amino ] pentanoic acid
WO2016149058A1 (en) 2015-03-17 2016-09-22 Merck Sharp & Dohme Corp. Triazolyl pyrimidinone compounds as pde2 inhibitors
US10358435B2 (en) 2015-03-17 2019-07-23 Merck Sharp & Dohme Corp. Triazolyl pyrimidinone compounds as PDE2 inhibitors
WO2016154081A1 (en) 2015-03-26 2016-09-29 Merck Sharp & Dohme Corp. Pyrazolyl pyrimidinone compounds as pde2 inhibitors
US10287269B2 (en) 2015-03-26 2019-05-14 Merck Sharp & Dohme Corp. Pyrazolyl pyrimidinone compounds as PDE2 inhibitors
US10195201B2 (en) 2015-05-05 2019-02-05 Merck Sharp & Dohme Corp. Heteroaryl-pyrimidinone compounds as PDE2 inhibitors
US10285989B2 (en) 2015-05-15 2019-05-14 Merck Sharp & Dohme Corp. Pyrimidinone amide compounds as PDE2 inhibitors
US10160762B2 (en) 2015-05-29 2018-12-25 Merck Sharp & Dohme Corp. 6-alkyl dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
US10174037B2 (en) 2015-06-04 2019-01-08 Merck Sharp & Dohme Corp. Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
US10647727B2 (en) 2015-06-25 2020-05-12 Merck Sharp & Dohme Corp. Substituted pyrazolo/imidazolo bicyclic compounds as PDE2 inhibitors
WO2016209749A1 (en) 2015-06-25 2016-12-29 Merck Sharp & Dohme Corp. Substituted pyrazolo/imidazolo bicyclic compounds as pde2 inhibitors
US10357481B2 (en) 2015-07-01 2019-07-23 Merck Sharp & Dohme Corp. Substituted triazolo bicyclic compounds as PDE2 inhibitors
US10287293B2 (en) 2015-07-01 2019-05-14 Merck Sharp & Dohme Corp. Bicyclic heterocyclic compounds as PDE2 inhibitors
WO2017108737A1 (en) 2015-12-23 2017-06-29 Chiesi Farmaceutici S.P.A. 1-(3-tert-butyl-phenyl)-3-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro- naphthalen-1-yl)-urea derivatives and their use as p38 mapk inhibitors
US10668035B2 (en) 2018-02-07 2020-06-02 Novartis Ag Substituted bisphenyl butanoic ester derivatives as NEP inhibitors
US11426375B2 (en) 2018-02-07 2022-08-30 Novartis Ag Substituted bisphenyl butanoic ester derivatives as NEP inhibitors
WO2020110011A1 (en) 2018-11-27 2020-06-04 Novartis Ag Cyclic peptides as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders
WO2020110008A1 (en) 2018-11-27 2020-06-04 Novartis Ag Cyclic pentamer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorder
WO2020110009A1 (en) 2018-11-27 2020-06-04 Novartis Ag Cyclic tetramer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders
WO2023084449A1 (en) 2021-11-12 2023-05-19 Novartis Ag Diaminocyclopentylpyridine derivatives for the treatment of a disease or disorder

Also Published As

Publication number Publication date
TW201100076A (en) 2011-01-01
CN103896796A (en) 2014-07-02
AU2010251967B9 (en) 2014-04-03
CA2763572A1 (en) 2010-12-02
MA33636B1 (en) 2012-10-01
EP2435409A1 (en) 2012-04-04
EP2594557A1 (en) 2013-05-22
AU2010251967B2 (en) 2013-04-18
US20130096127A1 (en) 2013-04-18
PT2435409E (en) 2014-11-05
EA201101671A1 (en) 2012-07-30
GT201100303A (en) 2014-03-14
UY32662A (en) 2010-12-31
MX2011012628A (en) 2011-12-14
CN103896796B (en) 2016-04-27
IL216367A0 (en) 2012-01-31
JO2962B1 (en) 2016-03-15
US20140296240A1 (en) 2014-10-02
SI2435409T1 (en) 2014-12-31
ES2602902T3 (en) 2017-02-22
CR20110616A (en) 2012-01-04
SMT201400175B (en) 2015-01-15
RS53664B1 (en) 2015-04-30
JP2012528113A (en) 2012-11-12
JP5420761B2 (en) 2014-02-19
MY156270A (en) 2016-01-29
PL2435409T3 (en) 2015-01-30
CU20110217A7 (en) 2012-03-15
NZ596304A (en) 2014-01-31
EA019511B1 (en) 2014-04-30
HRP20141050T1 (en) 2014-12-19
ECSP11011560A (en) 2012-01-31
DK2435409T3 (en) 2014-10-27
ES2602826T3 (en) 2017-02-22
AU2010251967A1 (en) 2011-12-08
CN102574801A (en) 2012-07-11
CN102574801B (en) 2016-04-27
US8394853B2 (en) 2013-03-12
ES2523734T3 (en) 2014-12-01
CO6470847A2 (en) 2012-06-29
ZA201108222B (en) 2012-07-25
SG176009A1 (en) 2011-12-29
EP2594556A1 (en) 2013-05-22
HN2011003097A (en) 2015-08-10
BRPI1011657A2 (en) 2019-04-16
ME01923B (en) 2015-05-20
PE20120330A1 (en) 2012-04-17
CU24051B1 (en) 2014-12-26
US8822534B2 (en) 2014-09-02
EP2594557B1 (en) 2016-08-10
TWI445530B (en) 2014-07-21
KR20120041703A (en) 2012-05-02
EP2435409B1 (en) 2014-08-13
CL2011002990A1 (en) 2012-08-31
AR076707A1 (en) 2011-06-29
US20100305131A1 (en) 2010-12-02
CA2763572C (en) 2017-10-17
KR101442897B1 (en) 2014-09-23
EP2594556B1 (en) 2016-08-10

Similar Documents

Publication Publication Date Title
EP2435409B1 (en) Substituted aminopropionic derivatives as neprilysin inhibitors
US9603819B2 (en) Substituted aminobutyric derivatives as neprilysin inhibitors
AU2010320930B2 (en) Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8877815B2 (en) Substituted carbamoylcycloalkyl acetic acid derivatives as NEP
EP2640375A1 (en) Method of treating contrast-induced nephropathy

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201080032688.1

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10720165

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 596304

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2010251967

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 002004-2011

Country of ref document: PE

Ref document number: CR2011-000616

Country of ref document: CR

WWE Wipo information: entry into national phase

Ref document number: 9188/DELNP/2011

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2763572

Country of ref document: CA

Ref document number: 2012512359

Country of ref document: JP

Ref document number: MX/A/2011/012628

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 11165101

Country of ref document: CO

Ref document number: 2010720165

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2010251967

Country of ref document: AU

Date of ref document: 20100526

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 201101671

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: A201114061

Country of ref document: UA

ENP Entry into the national phase

Ref document number: 20117031124

Country of ref document: KR

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: PI1011657

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: P-2014/0576

Country of ref document: RS

ENP Entry into the national phase

Ref document number: PI1011657

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20111125